 Introduction

 Structure

 Function

 Regulation/Control

Introduction
For many years glycoproteins have been a subject of interest. However, it is in the second half of
this century that they have aroused the interest of biochemists and biologists from a wide range
of fields. This increased interest is partly due to the fact that glycoproteins were discovered to be
abundant in living organisms. It is also due to the diverse functions of glycoproteins;
glycoproteins appear in nearly every biological process studied.
Many glycoproteins have structural functions. One of many instances is their role as a
constituent of the cell wall. Glycoproteins also form connective tissues such as collagen. They
are also found in gastrointestinal mucus secretions. Glycoproteins are used as protective agents
and lubricants. They are also found abundantly in the blood plasma where they serve many
functions.
The diverse function of glycoproteins is a direct result of their structure. These macromolecules
are composed of a peptide chain with one or more carbohydrate moieties. There are two broad
categories of glycoprotein structure. The carbohydrates are either linked N-glycosidically or O-
glycosidically to their constituent protein. Within these broader categories, there can be fine
structural differences which account for the large diversity of functions among glycoproteins.
Controlling of glycoproteins is achieved through synthesis and degradation. Those processes are
controlled by very specific enzymes. Not so much is yet researched on glycoprotein regulation in
general.

Structure
Structurally, glycoproteins consist of a polypeptide covalently bonded to a carbohydrate moiety.
The carbohydrate can make up anywhere from less than one percent to more than 80 percent of
the total protein mass. The saccharide chains, referred to as glycans, can be linked to the
polypeptide in two major ways. The first class of glycoproteins are the O-linked glycans. These
usually contain an N-acetylgalactosamine which is attached through a glycosidic bond to the O-
terminus of either threonine or serine. The other class of glycoproteins are the N-linked glycans.
These involve a glycosidic bond between N-acetylglucosamine and the N-terminus of an
asparagine residue (Mathews 291 and Schulz 228-230).
As stated above, O-linked glycans consist of N-acetylgalactosamine attached to the O-terminus
of a threonine or serine residue. N-acetylgalactosamine is simply a galactose molecule with an
amine group covalently bonded to the second carbon. This amine group is bonded to a carboxyl
group. N-acetylgalactosamine attaches to the carboxyl group of the amino acid through the
hydroxyl group of its anomeric carbon. Another type of O-linked glycan consists of a galactose
or a glucosyl-galactose disaccharide linked to the hydroxyl of hydroxylysine. Yet another type of
O-linkage involves the binding of arabinose to the hydroxyl of hydroxyproline. In all of the 0-
linked glycans, there can be a variety of different monosaccharide or polysaccharide chains
attached to the sugar that is bonded to the amino acid (Mathews 293 and Lennarz 6-10).
The other class of glycoproteins are N-linked glycans. These molecules consist of an N-
acetylglucosamine bonded to the amide nitrogen of an asparagine molecule. N-
acetylglucosamine is simply a glucose molecule which is bonded to an amine group. This amine
group, in turn, is bonded to a hydroxyl group. The N-acetylglucosamine is bonded to the
asparagine through its anomeric carbon. The asparagine must be surrounded by a specific amino
acid sequence, or sequon. This sequence is -X-Asn-X-Thr; the X can be any amino acid. A large
variety of polysaccharide side chains can be linked to the N-acetylglucosamine. A typical
polysaccharide chain is Man2 a(1-6)-Man B(1-4)-GlcNAc B(1-4)-GlcNAc B(1-N) Asn. Adding
on to this structure can create many different N-linked glycans (Mathews 293 and Lennarz 10-
11).
The carbohydrate chains of glycoproteins can play a role in the structure of the polypeptide. For
example, in human immunoglobulins, the carbohydrate chain wraps around one of the protein
domains. By doing so it prevents contact of this domain with the neighboring domain. An
experiment that was done by Koide et al illustrates how the carbohydrate can change the overall
structure of the polypeptide. The carbohydrate side chains of a rabbit antibody were removed
through glycosidase digestion. The result was that the domain where the carbohydrate had
previously been attached could no longer perform its ordinary function. Because an
immunoglobulin's function is determined to a large extent by its structure, it can be concluded
that removing the carbohydrate affected the structure of the molecule (Lennarz 25-27).

Function
Because carbohydrates and proteins by themselves serve in a vast number of biological
functions, it should not be surprising that linking the two together results in a macromolecule
with an extremely large number of functions. Because of this and their biologically ubiquitous
nature, the best way to go about exploring glycoprotein function is to break it down into
categories that are fairly general. The following is an attempt to do this.
Structural: Glycoproteins are found throughout matrices. They act as receptors on cell surfaces
that bring other cells and proteins (collagen) together giving strength and support to a matrix
(Ivatt).
Proteoglycan-linking glycoproteins cross links proteoglycan molecules and is involved in the
formation of the ordered structure within cartilage tissue. In nerve tissue glycoproteins are
abundant in gray matter and appear to be associated with synaptosomes, axons, and microsomes.
Prothrombin, thrombin, and fibrinogen are all glycoproteins that play an intricate role in the
blood clotting mechanism (Gottschalk). In certain bacteria the slime layer that surrounds the
outermost components of cell walls are made up of glycoproteins of high molecular weight. In
addition to forming these s-layers, glycoproteins also function as bacterial flagella. These are
made up of bundles of glycoproteins protruding from the cell's surface. Their rotation provides
propulsion. In plants, glycoproteins have roles in cell wall formation, tissue differentiation,
embryogenesis, and sexual adhesion (certain algal species) (Montreuil).
Protection: High molecular weight polymers called mucins are found on internal epithelial
surfaces. They form a highly viscous gel that protects epithelium form chemical, physical, and
microbial disturbances. Examples of mucin sites are the human digestive tract, urinary tract, and
respiratory tracts. "Cervical mucin" is a glycoprotein found in the cervix of animals that regulates
access of spermatozoa to the upper reproductive tract. Recently it was discovered that mucins
may be responsible for aiding in metastasis of transformed cancer cells (Ivatt). Mucins are also
found on the outer body surfaces of fish to protect the skin (Gottschalk). Not only does mucin
serve the function of protection, but it also acts as a lubricant. Human lacrimal glands produce a
glycoprotein which protects the corneal epithelium from desiccation and foreign particles.
Human sweat glands secrete glycoproteins which protect the skin from the other excretory
products that could harm the skin (Gottschalk).
Reproduction: Glycoproteins found on the surface of spermatozoa appear to increase a sperm
cell's attraction for the egg by altering the electrophoretic mobility of the plasma membrane.
Actual binding of the sperm cell to the egg is mediated by )-linked glycoproteins serving as
receptors on the surface of each the two membranes. The zona pellucida is an envelope made of
glycoprotein that surrounds the egg and prevents polyspermy from occurring after the first sperm
cell has penetrated the egg's plasma membrane (Ivatt). Hen ovalbumin is a glycoprotein found in
egg white that serves as a food storage unit for the embryo (Mathews).
Adhesion: Glycoproteins serve to adhere cells to cells and cells to substratum. Cell-cell adhesion
is the basis for the development of functional tissues in the body. The interactions between cells
is mediated by the glycoproteins on those cell's surfaces. In different domains of the body,
different glycoproteins act to unite cells. For example, nerve cells recognize and bind to one
another via the glycoprotein N-CAM (nerve cell adhesion molecule). N-CAM is also found on
muscle cells indicating a role in the formation of myoneural junctions. With cell-substratum
adhesion, glycoproteins serve as cell surface receptors for certain adhesion ligands that mediate
and coordinate the interaction of cells. Substrates with the appropriate receptor will bind to the
cell related to that receptor. For example, a substrate containing the glycoprotein fibronectin will
be recognized and adhered to by fibroblasts. The fibroblasts will then secrete adhesion molecules
and continue to spread, producing a pericellular matrix (Ivatt).
Hormones: There are many glycoproteins that function as hormones such as human chorionic
gonadotropin (HCG) which is present in human pregnancy urine. Another example is
erythropoietin which regulates erythrocyte production (Gottschalk).
Enzymes: Glycoprotein enzymes are of three types. These are oxidoreductases, transferases, and
hydrolases(Gottschalk).
Carriers: Glycoproteins can bind to certain molecules and serve as vehicles of transport. They
can bind to vitamins, hormones, cations, and other substances.
Inhibitors: Many glycoproteins in blood plasma have shown antiproteolytic activity. For
example, the glycoprotein a1-antichymotrypsin inhibits chymotrypsin.
Defense: In beetles pygidial glands secrete a glycoprotein disinfecting paste that covers the body
and hardens. This shell provides protection against attack by bacteria and fungi (Gottschalk).
Freezing-point depression: Glycoproteins were found in the sera of antarctic fishes to decrease
the freezing point due to their apparent interaction with water(Gottschalk).
Vision: In bovine visual pigment a glycoprotein forms the outer membranes of retinal rods
(Gottschalk).
Immunological: The interaction of blood group substances with antibodies is determined by the
glycoproteins on erythrocytes. Adding or removing just one monosaccharide from a blood group
structure, the antigenicity and therefore a person's blood type can be altered (Ivatt). Many
immunoglobulins are actually glycoproteins (Gottschalk). Soluble immune mediators such as
helper, suppressor, and activator cell have been shown to bind to glycoproteins found on the
surface of their target cells. B and T cells contain surface glycoproteins that attract bacteria to
these sites and bind them. In much the same manner, glycoproteins can direct phagocytosis.
Because the HIV virus recognizes the receptor protein CD4, it binds to helper T cells which
contain it. (Montreuil, et al).

Regulation/Control
Regulation and control of glycoproteins is not as straight forward as some might think. "If
someone was to understand regulation in glycoproteins he would have to look at the enzymes
that are involved in the biosynthesis pathway of these molecules; what is affecting the enzyme
activity (could be hormonal). The big interest in this area is in the cloning of the genes, the
cloning of the enzymes that are involved in the synthesis of the oligosaccharide on the
glycoproteins. Unfortunately, not that much is known on the above subject" Dr. Roger
Bretthauer
On the other hand, control of glycoproteins can be seen through biosynthesis and degradation.
Here, the biosynthesis and degradation of the N-linked glycoproteins will be emphasized.
Synthesis
The protein part of the glycoprotein is formed at the ribosomes, where all proteins are
synthesized, on template represented by RNA and DNA. As a result, its structure can change
only through the mutation of the genetic material of the cell. On the other hand, the carbohydrate
component of a glycoprotein is not a product of the ribosome; it is synthesized somewhere in the
cytoplasm, but the exact site of synthesis has not yet been established. Since it is not directly
genetically controlled, the oligosaccharide part shows a much greater variation (Scientific
American).
In contrast with O-linked glycoproteins, where oligosaccharide assemble occurs on the
polypeptide chain, N-linked glycoproteins assemble their oligosaccharide portions on a lipid
linked intermediate, dolichol phosphate. The first step in oligosaccharide synthesis is the
formation of that intermediate. In subsequent steps, sugars, the first being always N-
acetylglucosamine (GlcNAc), are chain-like connected to dolichol phosphate. One more GlcNAc
and three more mannose sugars are linked to the first GlcNAc to form the typical core of N-
linked glycoproteins. Addition of any other sugar can be in any possible combination, according
to the desired resulting functions. The specificity of the enzymes is very important in the
synthesis process. Every sugar added, is catalyzed by a different enzyme. These group of
enzymes are called glycosyltransferases (example Name). The first addition of GlcNAc to
dolichol phosphate is catalyzed by the specific enzyme example) that cleave peptide bonds, and
glycosidases (e.g example). enzymes that remove sugars one at a time from the end of an
oligosaccharide chain. Both of these groups are contained in lysozomes. The lysosome attaches
to a phagocyte, which has engulfed a substance that needs to be broken down, and releases its
enzymes in it(Gottschalk). Next, these enzymes begin their catalytic action. In degradation, ad in
synthesis, the enzymes involved are very specific. After the glycoprotein is broken down, its
amino acid and sugar components are either metabolized or can be used in the formation of
another glycoprotein. Enzymatic degradation can provide much information about the structure
of the oligosaccharide chains, as well as about the carbohydrate peptide linkage. For example, if
a glycoprotein is treated with mannosidase (removes mannose), and mannose is released, one can
conclude that mannose residues were located at the periphery of the molecule since glycosidases
remove sugars from the end of the oligosaccharide chain (Scientific American).
Regulation and control is the organism's ultimate tool to monitor and adjust the production or
degradation of different molecules. Like a factory, it would be useless and inefficient to produce
excess products when there is no need for them. On the other hand, shortage of products could be
a problem too. Hopefully, further research will put some light in the area of glycoprotein
regulation.
For a more detailed analysis on the biosynthesis and regulation of glycoproteins, the reader is
referred to one of the journal articles in the bibliography.
Works Cited
Personal communications. Bretthauer, Roger K. Professor of Biochemistry Indiana
University. interview at 11/28/95. Phone (219) 631-7348. Netscape :
[Link]

Evans, Ronald M. "The steroid and Thyroid Hormone Receptor Superfamily." Science. 40
(1988): 889-894.
Gottschalk, Alfred. Glycoproteins. Their Composition, Structure, and function. Elsevier
Publishing Company: New York, 1972.
Herrera H., and E.M Rodriguez. "Secretory Glycoproteins of the Rat Subcommisoral Organ Are
N-Linked Complex-Type Glycoproteins. Demonstration by Combined Use of Lectins and
Specific Glycosidases, and by the Administration of Tunicamycin. Histochemistry. 93 (1990):
607-615.
Herscovics Annete, and Peter Orlean. "Glycoprotein Biosynthesis in Yeast." FASEB Journal 7
(1993): 540-550.
Ivatt, Raymond J. The Biology of Glycoproteins. Plenum Press: New York, 1984. Kornfeld
Rosaline, and Stuart Kornfeld. "Assembly of Asparagine-Linked Oligosaccharide." Annual
Review of Biochemistry 54 (1985): 631-664.
Langan Thomas J., and Mary C. Slater. "Isoprenoids and Astroglial Cell Cycling: Diminished
Mevalonate Availability and Inhibition of Dolichol-Linked Glycoprotein Synthesis Arrest
Cycling Through Distinct Mechanisms". Journal of Cellular Physiology 149 (1991): 284- 292.
Lennarz, William J. The Biochemistry of Glycoproteins and Proteoglycans. Plenum Press: New
York, 1980.
Mathews, Christopher K., and K.E. van Holde. Biochemistry. The Benjamin/Cummings
Publishing Company, Inc.: Redwood City, 1990.
Montreuil, J., Vliegenthart, J.F.G., and Schachter, H. Glycoproteins. Elsevier: Amsterdam, 1995.
Qiu Zhiyong, and Frank Tufaro and Shirley Gillam. "Brefeldin A and Monensin Arrest Cell
Surface Expression of Membrane Glycoproteins and Release of Rubella Virus". Journal of
General Virology 76 (1995): 885-863.
Sharon, Nathan. Glycoproteins." Scientific American. May (1974): 78-86.
Schulz, Georg E. And R.H. Schirmer. Principles of Protein Structure. Springer-Verlag: New
York, 1979.
Zhu Xiaying, and Yucheng Zeng, and Mark A. Lehrman. "Evidence That the Hamster
Tunicamycin Resistence Gene Encodes UDP-GlcNac:Dolichol Phosphate N-
Acetylglucosamine-1-phosphate Transferase". The Journal of Biological Chemistry 267 (1992):
8895-8902.

LINKS
Glycoprotein Structure and Steroid Hormone Function
Glycoproteins play an important part in hormone function. The action of hormones depends on
the initial binding of the hormone to a protein receptor molecule. In many cases this molecule is
a glycoprotein. Many hormones bind to receptors in the cell membrane; these hormones never
actually enter the cell. Steroids, on the other hand, bind to an intracellular protein receptor. There
is still controversy over whether the steroid hormone receptor is found in the nucleus or the
cytosol. However, it is clear that after the steroid binds, the hormone-receptor complex moves to
the nucleus. The hormone binding domain of the receptor is found at the C-terminus. The amino
acid sequence of this region is highly diverse; it is not conserved from one protein to the next.
Binding of the hormone stimulates a conformational change in the hormone receptor. This
change allows the hormone-receptor complex to bind to the DNA. The DNA binding domain is
highly conserved and is found within the central core of the protein. The central core contains a
very basic amino acid sequence. In the cellular environment, these bases will tend to pick up a
hydrogen and become positively charged. The positive charge will attract the hormone-receptor
complex to the negatively charged DNA. Binding of the complex to the DNA stimulates
transcription (Evans 890-891 and Mathews 808-809).
Similarities Between Glycoproteins, Cytochromes, and Metalloenzymes
Cytochromes have features that are quite similar to transferrins, a particular class of
glycoproteins. First of all, cytochromes make up some of the integral proteins found in
membranes, as do glycoproteins. Second of all, the main function of cytochromes is the binding
of ion cations. Via oxidoreduction with these cations of 2+state, cytochromes bind iron to a
porphyrin prosthetic group, forming a heme group (Mathews). The function is to transport
cations in and out of the cell. Transferrin is an iron binding protein as well. It interacts with iron
cations of the 2+state which also bind to a porphyrin group, Protoporphyrin IX, to form a heme
group. Transferrins carry ions to many different locations in the body including in and out of
cells (Gottschalk). Another group of molecules that serve a function related to glycoproteins are
the metalloenzymes. These enzymes, as their name implies, bind to metal ions via the same type
of heme groups just discussed (Gottschalk). One class of glycoprotein enzymes, the
oxidoreductases, contain an enzyme called chloroperoxidase. Like transferrin, chloroperoxidase
contains protophyrin IX and forms the heme group with iron 3+ (Mathews). Eicosanoids, are
also related to glycoproteins because they recognize the receptors on cells which are
glycoproteins.
Inhibition of asparagine linked glycoproteins by antibiotics
Synthesis of N-linked glycoproteins can be inhibited with the use of antibiotics
(function of antibiotics). Examples are monensin, mevinolin and tunicamycin.
Monensin, a monocovalent ionophore, inhibits the transport of proteins through the
endoplasmic reticulum- Golgi complex (general virology 855). Mevinolin on the
other hand, is an inhibitor of mevalonate synthesis. Mevalonate is the precursor of
dolichol and other isoprenoid lipids (cellular physiology 284). Finally, as mentioned
above, asparagine linked glycosylation involves the first step of addition of GlcNAc
to dolichol diphosphate. This reaction is catalyzed by the enzyme UDP-
GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase or GPT .
Tunicamycin is a specific inhibitor of GPT, therefore it can inhibit the synthesis of all
N-linked glycoproteins (biological chemistry 8895). To give just an example of the
effectiveness of tunicamycin, when it was injected to rats' hearts, it killed 12, 24,
50, and 60 h after the injection (histochemistry 607). Another connection could be
seen with the function of the ribosomes, since the polypeptide chain of all
glycoproteins is made there.
glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to
polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or
posttranslational modification. This process is known as glycosylation. In proteins that have
segments extending extracellularly, the extracellular segments are often glycosylated.
Glycoproteins are often important integral membrane proteins, where they play a role in cell-cell
interactions. Glycoproteins also occur in the cytosol, but their functions and the pathways
producing these modifications in this compartment are less well-understood.[2]

Contents
[hide]
• 1 N-glycosylation and O-glycosylation
• 2 Monosaccharides
• 3 Examples
• 4 Hormones
• 5 Functions
• 6 Analysis
• 7 See also
• 8 References
• 9 External links

[edit] N-glycosylation and O-glycosylation

There are two types of glycoproteins:
• In N-glycosylation (see on the right), the addition of sugar chains can happen at the
amide nitrogen on the side chain of the asparagine.
• In O-glycosylation, the addition of sugar chains can happen on the hydroxyl oxygen on
the side chain of hydroxylysine, hydroxyproline, serine, or threonine.
[edit] Monosaccharides
The eight sugars contained in glycoproteins.
Monosaccharides commonly found in eukaryotic glycoproteins include:[3]
The principal sugars found in human glycoproteins[4]
Sugar Type Abbreviation
β-D-Glucose Hexose Glc
β-D-Galactose Hexose Gal
β-D-Mannose Hexose Man
α-L-Fucose Deoxyhexose Fuc
N-Acetylgalactosamine Aminohexose GalNAc
N-Acetylglucosamine Aminohexose GlcNAc
Aminononulosonic acid
N-Acetylneuraminic acid NeuNAc
(Sialic acid)
Xylose Pentose Xyl
The sugar group(s) can assist in protein folding or improve proteins' stability.
[edit] Examples
One example of glycoproteins found in the body is mucins, which are secreted in the mucus of
the respiratory and digestive tracts. The sugars attached to mucins give them considerable water-
holding capacity and also make them resistant to proteolysis by digestive enzymes.
Glycoproteins are important for white blood cell recognition, especially in mammals.[citation needed]
Examples of glycoproteins in the immune system are:
• molecules such as antibodies (immunoglobulins), which interact directly with antigens.
• molecules of the major histocompatibility complex (or MHC), which are expressed on the
surface of cells and interact with T cells as part of the adaptive immune response.
Other examples of glycoproteins include:
• glycoprotein IIb/IIIa, an integrin found on platelets that is required for normal platelet
aggregation and adherence to the endothelium.
• components of the zona pellucida, which surrounds the oocyte, and is important for
sperm-egg interaction.
 • structural glycoproteins, which occur in connective tissue. These help bind together the
fibers, cells, and ground substance of connective tissue. They may also help components
of the tissue bind to inorganic substances, such as calcium in bone.
• Glycoprotein-41 (gp41) and glycoprotein-120 (gp120) are HIV viral coat proteins.
Soluble glycoproteins often show a high viscosity, for example, in egg white and blood plasma.
• Miraculin which alters human tongue receptors to recognize sour foods as sweet.
[edit] Hormones
Hormones that are glycoproteins include:
• Follicle-stimulating hormone
• Luteinizing hormone
• Thyroid-stimulating hormone
• Human chorionic gonadotropin
• Alpha-fetoprotein
• Erythropoietin (EPO)
[edit] Functions 8925963985
Some functions served by glycoproteins[5]
Function Glycoproteins
Structural molecule Collagens
Lubricant and protective
Mucins
agent
Transport molecule Transferrin, ceruloplasmin
Immunologic molecule Immunoglobins, histocompatibility antigens
Human chorionic gonadotropin (HCG), thyroid-stimulating hormone
Hormone
(TSH)
Enzyme Various, e.g., alkaline phosphatase
Cell attachment- Various proteins involved in cell-cell (e.g., sperm-oocyte), virus-cell,
recognition site bacterium-cell, and hormone cell interactions
Antifreeze protein Certain plasma proteins of coldwater fish
Interact with specific
Lectins, selectins (cell adhesion lectins), antibodies
carbohydrates
Receptor Various proteins involved in hormone and drug action
Affect folding of certain
Calnexin, calreticulin
proteins
Regulation of
Notch and its analogs, key proteins in development
development
Hemostasis (and
Specific glycoproteins on the surface membranes of platelets
thrombosis)

[edit] Analysis
A variety of methods used in detection, purification, and structural analysis of glycoproteins
are[6][7]
Some important methods used to study glycoproteins
Method Use
Detects glycoproteins as pink bands after electrophoretic
Periodic acid-Schiff stain
separation.
Incubation of cultured cells with
Leads to detection of a radioactive sugar after electrophoretic
glycoproteins as radioactive
separation.
decay bands
Treatment with appropriate endo- Resultant shifts in electrophoretic migration help distinguish
or exoglycosidase or among proteins with N-glycan, O-glycan, or GPI linkages and
phospholipases also between high mannose and complex N-glycans.
Agarose-lectin column
To purify glycoproteins or glycopeptides that bind the
chromatography, lectin affinity
particular lectin used.
chromatography
Resultant shifts in electrophoretic migration help distinguish
Lectin affinity electrophoresis and characterize glycoforms, i.e. variants of a glycoprotein
differing in carbohydrate.
Compositional analysis following Identifies sugars that the glycoprotein contains and their
acid hydrolysis stoichiometry.
Provides information on molecular mass, composition,
Mass spectrometry
sequence, and sometimes branching of a glycan chain.
To identify specific sugars, their sequence, linkages, and the
NMR spectroscopy
anomeric nature of glycosidic chain.
Measures the mechanisms underlying the biomolecular
Dual Polarisation Interferometry interactions, including reaction rates, affinities and associated
conformational changes.
Methylation (linkage) analysis To determine linkage between sugars.
Amino acid or cDNA sequencing Determination of amino acid sequence.

[edit] See also

• P-glycoprotein
• Glycopeptide
• Proteoglycan
• Glycocalyx
• Gp120
• Gp41
• Miraculin
• Female Sperm Storage
P-glycoprotein
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ATP-binding cassette, sub-family B

(MDR/TAP), member 1

Crystallographic structure of the mouse MDR3

protein. The approximate positioning of the
protein in the cell membrane is indicated by the
blue (extracellular face) and red (cytoplasmic
face) lines. The protein is depicted as a rainbow
colored cartoon (N-terminus = blue, C-terminus
= red). A cyclic peptide inhibitor QZ59 is
represented by a space-filling model.[1]

[show]Available structures

PDB 3G5U, 3G60, 3G61

Identifiers

Symbol ABCB1; ABC20; CD243; CLCS; GP170;

s MDR1; MGC163296; P-gp; PGY1

OMIM: 171050 MGI: 97570

Externa
HomoloGene: 55496 GeneCards:
l IDs
ABCB1 Gene

[show]Gene Ontology
 • nucleotide binding
• transporter activity
• ATP binding
Molecular function
• xenobiotic-
transporting ATPase
activity
• hydrolase activity
• ATPase activity
• membrane fraction
• cell surface
Cellular
component
• membrane
• integral to
membrane

• transport
Biological process
• response to drug
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

 Orthologs

Species Human Mouse

Entrez 5243 18671

Ensemb ENSG000000855 ENSMUSG00000040

l 63 584

UniProt P08183 Q9QX25

RefSeq
NM_000927 NM_011076
(mRNA)

RefSeq
(protein NP_000918 NP_035206
)

Locatio
Chr 7: Chr 5:
n
86.97 - 87.18 Mb 8.67 - 8.75 Mb
(UCSC)

PubMed
[1] [2]
search

ABCB1 at EBI Gene

Expression Atlas

ABCB1 is differentially
expressed in 97
experiments [93 up/106
dn]: 26 organism parts:
kidney [2 up/0 dn], bone
marrow [0 up/2 dn], ...;
29 disease states:
normal [10 up/3 dn],
glioblastoma [0 up/2
dn], ...; 30 cell types, 22
cell lines, 11 compound
treatments and 16 other
conditions.

Factor Up/Do
Factor
Value wn

Legend: - number of
studies the gene is
up/down in

Diseas
Normal 10/3
e state

Compo
und
None 3/0
treatm
ent

Stromal Cell
1/2
cell type

Cell
Kidney 2/0
type

MDA- Cell
0/2
MB-231 line

Glioblas Diseas
0/2
toma e state

Epitheli Cell
0/2
al cell type

Cell
HeLa 0/2
line

Diseas
Primary e 2/0
staging

Organi
Bone
sm 0/2
marrow
part

ABCB1 expression data

in ATLAS
P-glycoprotein (permeability glycoprotein, abbreviated as P-gp or Pgp) is a well-characterized
ABC-transporter of the MDR/TAP subfamily.[2] P-gp is also called ABCB1, ATP-binding
cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been
designated CD243 (cluster of differentiation 243). In humans, P-glycoprotein is encoded by the
ABCB1 gene.[3]
Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal
proximal tubular cells, adrenal gland and capillary endothelial cells comprising the blood-brain
and blood-testis barrier.

Contents
[hide]
• 1 Function
• 2 Structure
• 3 Mechanism
• 4 Tissue distribution
• 5 Detecting the activity of the
transporter
• 6 History
• 7 See also
• 8 References
• 9 Further reading
• 10 External links

[edit] Function
The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-
binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and
intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1,
MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP
subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The
protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds
with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-
resistant cells and often mediates the development of resistance to anticancer drugs. This protein
also functions as a transporter in the blood-brain barrier.[4]
ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a
defense mechanism against harmful substances.
ABCB1 transports various substrates across the cell membrane including:
• Drugs such as colchicine, tacrolimus and quinidine
• Chemotherapeutic agents such as etoposide, doxorubicin, and vinblastine
• Lipids
• Steroids
• Xenobiotics
 • Peptides
• Bilirubin
• Cardiac glycosides like digoxin
• Immunosuppressive agents
• Glucocorticoids like dexamethasone
• HIV-type 1 antiretroviral therapy agents like protease inhibitors and
nonnucleoside reverse transcriptase inhibitors.
Its ability to transport the above substrates accounts for the many roles of ABCB1
including:
• Regulating the distribution and bioavailability of drugs
○ Increased intestinal expression of P-glycoprotein can reduce the
absorption of drugs that are substrates for P-glycoprotein. Thus, there
is a reduced bioavailability, and therapeutic plasma concentrations are
not attained. On the other hand, supratherapeutic plasma
concentrations and drug toxicity may result because of decreased P-
glycoprotein expression
○ Active cellular transport of antineoplastics resulting in multidrug
resistance to these drugs
• The removal of toxic metabolites and xenobiotics from cells into urine, bile,
and the intestinal lumen
• The transport of compounds out of the brain across the blood-brain barrier
• Digoxin uptake
• Prevention of ivermectin entry into the central nervous system
• The migration of dendritic cells
• Protection of hematopoietic stem cells from toxins.[2]

[edit] Structure
Pgp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal
glycosylation. The N-term half of the molecule contains 6 transmembrane domains, followed by
a large cytoplasmic domain with an ATP-binding site, and then a second section with 6
transmembrane domains and an ATP-binding site that shows over 65% of amino acid similarity
with the first half of the polypeptide.[5] In 2009, the first structure of a mammalian P-glycoprotein
was solved (3G5U).[6] The structure was derived from the mouse MDR3 gene product
heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to
structures of the bacterial ABC transporter MsbA (3B5W and 3B5X) [7] that adopt an inward
facing conformation that is believed to be important for binding substrate along the inner leaflet
of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the
binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding
pocket of P-gp is lined with aromatic amino acid side chains.
[edit] Mechanism
Binding of a substrate and ATP molecule occur simulatenously. Following binding of each, ATP
hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the
phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP
is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and
release of ADP and a phosphate molecule resets the protein.
[edit] Tissue distribution
P-glycoprotein is expressed primarily in certain cell types in the liver, pancreas, kidney, colon,
and jejunum.[8]
[edit]
lycoprotein Biosynthesis
Carbohydrates are added to proteins in a very complicated process which involves two
organelles, the endoplasmic reticulum and the Golgi apparatus. CHO addition to
proteins occurs both co- and post-translationally. The RNA coding the protein
sequence enters the cytoplasm where it binds to ribosomes (large RNA-protein
complexes) which are the site for protein synthesis. Cytoplasmic proteins are
synthesized on free ribosomes, but for future glycoproteins, the ribosomes bind to an
elongated, extensive organelle in the cell called the endoplasmic reticulum (ER).
Figure: ribosomes bind to an elongated, extensive organelle in the cell called the
endoplasmic reticulum (ER)
 (from web, searching for reference)

The nascent protein chain enters the lumen of the ER and a core oligosaccharide is
added to the protein. Further additions and removal (trimming and processing) of
monosaccharides are preformed in the lumen until a final core mannose structure has
been added. This is demonstrated in the animation below. (The pink two-lobbed
structure represents the ribosome which is bound to the ER membrane. The newly
synthesized protein is shown in the lumen side of the ER membrane. That is where
glycan transfer occurs.) The ER lumen contains high concentrations of molecular
chaperones to assist protein folding.
 • Animations of Glycoprotein Biosynthesis: Endoplasmic reticulum
Now additional carbohydrate modifications (post-translational) are made as the protein
moves from the lumen of the ER (probably by a budding process) to another series of
stacked, pancake-like organelles called the Golgi apparatus. Here terminal
carbohydrate modification is completed. The Golgi does not contain molecular
chaperons since protein folding is complete when the proteins arrive. Rather they have
high concentrations of membrane bound enzymes, including glycosidases, and
glycosyltransferases.
• Animations of Glycoprotein Biosynthesis: Golgi
Glyprotein Function
The role of CHO in glycoprotein structure/function is slowly being determined. The most
important seems to involve their role in directing proper folding of proteins in the ER
which accounts for the observations that glycan addition to proteins in the ER is a
cotranslational event. When inhibitors of ER glycosylation are added to cells, protein
misfolding and aggregation are observed. The extent of misfolding depends on the
particular protein and particular glycosylation sites with the protein. The polar CHO
residues help promote solubility of folding intermediates, similar to the effects of many
chaperone proteins.
The glycan moieties of the folding glycoprotein also lead to binding of the protein to
lectins in the ER which serve as molecular chaperones. The most studied of these
chaperones are involved in the calnexin-calreticulin cycle, and facilitate correct disulfide
bond formation in the protein. After two glucose residues are removed by glucosidase I and
II, the monoglucosylated protein binds to calnexin (CNX) and/or calreticulin (CRT), two
homologous ER lectins specific for monoglucosylated proteins. Once bound, another protein,
ERp57, a molecular chaperone with a disulfide bond (shown in diagram) interacts with
the protein. This protein has protein disulfide isomerase activity.
If a glycoprotein has not folded completely, it is recognized by a glycoprotein
glucosyltransferase, which adds a glucose to it. This then promotes reentry into the
calnexin/calreticulin cycle.
Ideally, unfolded or misfolded proteins would be targeted from degradation and
elimination from cells. The ER has evolved a system to accomplish this. Since folding
occurs in the ER, to prevent misfolding and aggregation, the ER also contains chaperones and
folding catalysts. Stress (such as through heat shock) stimulates ER chaperone activity. As a
final defense mechanism, unfolded or aberrantly-folded proteins are degraded by the cytoplasmic
proteasome complex. Nonnative forms of some proteins that "escape" this surveillance system
can accumulate and result in disease (for example neurodegenerative diseases like Alzheimers
and Parkinson's disease.
Glycobiology and Glycomics
Our understanding of the synthesis and structure of glycan portions of glycoproteins has
lagged behind our understanding of protein and nucleic acid structure and synthesis.
Several reasons account for this:
• carbohydrates are much more complex with more functional groups per carbon
and with a much larger number of stereocenters, making chemical synthesis and
structure determination more difficult.
• carbohydrate chain synthesis is not directed by a template as is the synthesis of
DNA, RNA, and proteins
• synthesis is spread over two different organelles, and which allows great
heterogeneity in main chain and branch chain synthesis, which provides
heterogeneous samples for analysis
New techniques in analysis and synthesis of carbohydrate analogs and inhibitors of
enzymes involved in CHO synthesis and degradation, as well as in genetic
manipulations of gene for these enzymes, are revolutionizing our understanding of the
function of carbohydrate groups on lipids and proteins. On a more practical note, new
methods to synthesize glycoproteins using recombinant DNA technology have been
developed that allow synthesis of therapeutic human glycoproteins in yeast. Although
they share many of the same synthetic steps, yeast glycoproteins are enriched n the
high-mannose type, making them targets of the human immune system. Human and
yeast glycoproteins synthesis produce the same mannose core in the ER (as illustrated
in the animation above). However, differences in synthesis occurs in the Golgi. Human
Golgi contain α -mannosidases I and II, which remove all but 3 Man residues from the
final product. In yeast, however, these mannosidases appear to be missing so more
Man residues are added (as many as 100). Human proteins made in yeast, therefore,
contain many Man residue, which are recognized by the human immune system. So
address these issues, Hamilton et al produced mutants of the yeast Pichia pastoris that
localized glycoprotein synthesis proteins for mannosidase I and II, as well as other
human glycoprotein synthesis genes, to the correct intracellular location while
inactivating normal yeast gene, resulting in the production of human glycoproteins with
the correct CHO structure in yeast. This may prove to have widespread use in the
production of therapeutic human proteins.

4/6/10
May et al conducted experiments to determine the mechanism that allows enzymes to synthesize
carbohydrate polymers of a defined length without a template (as in DNA, RNA, and protein
synthesis). In their experiments they used GlfT2, a galactofuranosyltransferase which catalyzes
the formation of galactan, a polymer of 20-40 galactofuranose (Gal f) residues that is an integral
part of the cell wall in mycobacteria.. They first looked to see if the enzyme could regulate
length by itself. To do this they used only the GlfT2 and the sugar with a synthetic lipid base
replacing the natural one. The experiment showed that he GlfT2 could make galactan of length
with a peak at 27 monomers by itself. They then wanted to know if GlfT2 used a processive
process (when the transferase releases the growing glycan after many rounds of addition of
monomer) or a distributive process (when the transferase releases the growing glycan after each
monomer addition). To do this they added a reagent that prevented the GlfT2 from rebinding to
a growing polymer after its release. Under these conditions, the only way the transferase could
make a large polymer was to never release it. The enzyme still formed long polymers,
suggesting that GlfT2 used a processive process. Yet how could an enzyme using a processive
process make a polymer with specific numbers of monomers?
The enzyme adds a monomeric Gal f that is activated for transfer by the addition of a small
molecule, UDP (similar to ADP). The Gal f is transferred to the growing glycan which has a
very long lipids attached to one end as part of its normal synthetic pathway. They attached
different length lipids to the first monomer. They found that if the lipid was too small the
enzyme would use a distributive process and the longer the lipid the longer the carbohydrate.
This indicates that there is an allosteric lipid binding site on the enzyme, which helps hold the
polymer while the enzyme works on it. The lipid, effectively a substrate tether, would effectively
decrease the apparent Kd (and perhaps Km) of the growing glycan for the enzyme. The
carbohydrate will release from the enzyme and stop growing when the rate of dissociation
increases beyond the rate of elongation. This means that the stronger the binding between the
enzyme and the lipid the longer the carbohydrate polymer. The way to increase the strength of
the lipid enzyme interaction is to increase the length the lipid so the length of the polymer is
proportional to the length of the lipid. Hence the length of the lipid that acts as an anchoring for
the growing polymer is what determines the length of the carbohydrate, and explains how there
can be control in carbohydrate polymerization without the need of a template.
Here is a recent (2005) list of glycomics/glycobiology web sites:
Glycomics consortiums:
• Functional Glycomics Gateway (Nature)
• Glycoarrays Consortium - UK: functional glycomics and CHO assays
Databases:
• Glycan Binding Protein database - CFG (similar to Swiss-Prot for proteins and GenBank
for genes
• Kyoto Encyclopedia of Genes and Genomes Glycan Database
• GlycoSuite (from Proteome Systems)
• [Link]
Misc:
• Glycobiology Resources
• Contemporary CHO Chemistry
• Essentials of Glycobiology - Book by NCBI ****
• or many years glycoproteins have been a subject of interest. However, it is in the second
half of this century that they have aroused the interest of biochemists and biologists from
a wide range of fields. This increased interest is partly due to the fact that glycoproteins
were discovered to be abundant in living organisms. It is also due to the diverse functions
of glycoproteins; glycoproteins appear in nearly every biological process studied.
• Many glycoproteins have structural functions. One of many instances is their role as a
constituent of the cell wall. Glycoproteins also form connective tissues such as collagen.
They are also found in gastrointestinal mucus secretions. Glycoproteins are used as
protective agents and lubricants. They are also found abundantly in the blood plasma
where they serve many functions.
• The diverse function of glycoproteins is a direct result of their structure. These
macromolecules are composed of a peptide chain with one or more carbohydrate
moieties. There are two broad categories of glycoprotein structure. The carbohydrates are
either linked N-glycosidically or O-glycosidically to their constituent protein. Within
these broader categories, there can be fine structural differences which account for the
large diversity of functions among glycoproteins.
• Controlling of glycoproteins is achieved through synthesis and degradation. Those
processes are controlled by very specific enzymes. Not so much is yet researched on
glycoprotein regulation in general.
•

• Structure
• Structurally, glycoproteins consist of a polypeptide covalently bonded to a carbohydrate
moiety. The carbohydrate can make up anywhere from less than one percent to more than
80 percent of the total protein mass. The saccharide chains, referred to as glycans, can be
linked to the polypeptide in two major ways. The first class of glycoproteins are the O-
linked glycans. These usually contain an N-acetylgalactosamine which is attached
through a glycosidic bond to the O-terminus of either threonine or serine. The other class
of glycoproteins are the N-linked glycans. These involve a glycosidic bond between N-
acetylglucosamine and the N-terminus of an asparagine residue (Mathews 291 and
Schulz 228-230).
• As stated above, O-linked glycans consist of N-acetylgalactosamine attached to the O-
terminus of a threonine or serine residue. N-acetylgalactosamine is simply a galactose
molecule with an amine group covalently bonded to the second carbon. This amine group
is bonded to a carboxyl group. N-acetylgalactosamine attaches to the carboxyl group of
the amino acid through the hydroxyl group of its anomeric carbon. Another type of O-
linked glycan consists of a galactose or a glucosyl-galactose disaccharide linked to the
hydroxyl of hydroxylysine. Yet another type of O-linkage involves the binding of
arabinose to the hydroxyl of hydroxyproline. In all of the 0-linked glycans, there can be a
variety of different monosaccharide or polysaccharide chains attached to the sugar that is
bonded to the amino acid (Mathews 293 and Lennarz 6-10).
• The other class of glycoproteins are N-linked glycans. These molecules consist of an N-
acetylglucosamine bonded to the amide nitrogen of an asparagine molecule. N-
acetylglucosamine is simply a glucose molecule which is bonded to an amine group. This
amine group, in turn, is bonded to a hydroxyl group. The N-acetylglucosamine is bonded
to the asparagine through its anomeric carbon. The asparagine must be surrounded by a
specific amino acid sequence, or sequon. This sequence is -X-Asn-X-Thr; the X can be
any amino acid. A large variety of polysaccharide side chains can be linked to the N-
acetylglucosamine. A typical polysaccharide chain is Man2 a(1-6)-Man B(1-4)-GlcNAc
B(1-4)-GlcNAc B(1-N) Asn. Adding on to this structure can create many different N-
linked glycans (Mathews 293 and Lennarz 10-11).
• The carbohydrate chains of glycoproteins can play a role in the structure of the
polypeptide. For example, in human immunoglobulins, the carbohydrate chain wraps
around one of the protein domains. By doing so it prevents contact of this domain with
the neighboring domain. An experiment that was done by Koide et al illustrates how the
carbohydrate can change the overall structure of the polypeptide. The carbohydrate side
chains of a rabbit antibody were removed through glycosidase digestion. The result was
that the domain where the carbohydrate had previously been attached could no longer
perform its ordinary function. Because an immunoglobulin's function is determined to a
large extent by its structure, it can be concluded that removing the carbohydrate affected
the structure of the molecule (Lennarz 25-27).
•

• Function
• Because carbohydrates and proteins by themselves serve in a vast number of biological
functions, it should not be surprising that linking the two together results in a
macromolecule with an extremely large number of functions. Because of this and their
biologically ubiquitous nature, the best way to go about exploring glycoprotein function
 is to break it down into categories that are fairly general. The following is an attempt to
do this.
• Structural: Glycoproteins are found throughout matrices. They act as receptors on cell
surfaces that bring other cells and proteins (collagen) together giving strength and support
to a matrix (Ivatt).
• Proteoglycan-linking glycoproteins cross links proteoglycan molecules and is involved in
the formation of the ordered structure within cartilage tissue. In nerve tissue
glycoproteins are abundant in gray matter and appear to be associated with
synaptosomes, axons, and microsomes. Prothrombin, thrombin, and fibrinogen are all
glycoproteins that play an intricate role in the blood clotting mechanism (Gottschalk). In
certain bacteria the slime layer that surrounds the outermost components of cell walls are
made up of glycoproteins of high molecular weight. In addition to forming these s-layers,
glycoproteins also function as bacterial flagella. These are made up of bundles of
glycoproteins protruding from the cell's surface. Their rotation provides propulsion. In
plants, glycoproteins have roles in cell wall formation, tissue differentiation,
embryogenesis, and sexual adhesion (certain algal species) (Montreuil).
• Protection: High molecular weight polymers called mucins are found on internal
epithelial surfaces. They form a highly viscous gel that protects epithelium form
chemical, physical, and microbial disturbances. Examples of mucin sites are the human
digestive tract, urinary tract, and respiratory tracts. "Cervical mucin" is a glycoprotein
found in the cervix of animals that regulates access of spermatozoa to the upper
reproductive tract. Recently it was discovered that mucins may be responsible for aiding
in metastasis of transformed cancer cells (Ivatt). Mucins are also found on the outer body
surfaces of fish to protect the skin (Gottschalk). Not only does mucin serve the function
of protection, but it also acts as a lubricant. Human lacrimal glands produce a
glycoprotein which protects the corneal epithelium from desiccation and foreign
particles. Human sweat glands secrete glycoproteins which protect the skin from the
other excretory products that could harm the skin (Gottschalk).
• Reproduction: Glycoproteins found on the surface of spermatozoa appear to increase a
sperm cell's attraction for the egg by altering the electrophoretic mobility of the plasma
membrane. Actual binding of the sperm cell to the egg is mediated by )-linked
glycoproteins serving as receptors on the surface of each the two membranes. The zona
pellucida is an envelope made of glycoprotein that surrounds the egg and prevents
polyspermy from occurring after the first sperm cell has penetrated the egg's plasma
membrane (Ivatt). Hen ovalbumin is a glycoprotein found in egg white that serves as a
food storage unit for the embryo (Mathews).
• Adhesion: Glycoproteins serve to adhere cells to cells and cells to substratum. Cell-cell
adhesion is the basis for the development of functional tissues in the body. The
interactions between cells is mediated by the glycoproteins on those cell's surfaces. In
different domains of the body, different glycoproteins act to unite cells. For example,
nerve cells recognize and bind to one another via the glycoprotein N-CAM (nerve cell
adhesion molecule). N-CAM is also found on muscle cells indicating a role in the
formation of myoneural junctions. With cell-substratum adhesion, glycoproteins serve as
cell surface receptors for certain adhesion ligands that mediate and coordinate the
interaction of cells. Substrates with the appropriate receptor will bind to the cell related to
that receptor. For example, a substrate containing the glycoprotein fibronectin will be
 recognized and adhered to by fibroblasts. The fibroblasts will then secrete adhesion
molecules and continue to spread, producing a pericellular matrix (Ivatt).
• Hormones: There are many glycoproteins that function as hormones such as human
chorionic gonadotropin (HCG) which is present in human pregnancy urine. Another
example is erythropoietin which regulates erythrocyte production (Gottschalk).
• Enzymes: Glycoprotein enzymes are of three types. These are oxidoreductases,
transferases, and hydrolases(Gottschalk).
• Carriers: Glycoproteins can bind to certain molecules and serve as vehicles of transport.
They can bind to vitamins, hormones, cations, and other substances.
• Inhibitors: Many glycoproteins in blood plasma have shown antiproteolytic activity. For
example, the glycoprotein a1-antichymotrypsin inhibits chymotrypsin.
• Defense: In beetles pygidial glands secrete a glycoprotein disinfecting paste that covers
the body and hardens. This shell provides protection against attack by bacteria and fungi
(Gottschalk).
• Freezing-point depression: Glycoproteins were found in the sera of antarctic fishes to
decrease the freezing point due to their apparent interaction with water(Gottschalk).
• Vision: In bovine visual pigment a glycoprotein forms the outer membranes of retinal
rods (Gottschalk).
• Immunological: The interaction of blood group substances with antibodies is determined
by the glycoproteins on erythrocytes. Adding or removing just one monosaccharide from
a blood group structure, the antigenicity and therefore a person's blood type can be
altered (Ivatt). Many immunoglobulins are actually glycoproteins (Gottschalk). Soluble
immune mediators such as helper, suppressor, and activator cell have been shown to bind
to glycoproteins found on the surface of their target cells. B and T cells contain surface
glycoproteins that attract bacteria to these sites and bind them. In much the same manner,
glycoproteins can direct phagocytosis. Because the HIV virus recognizes the receptor
protein CD4, it binds to helper T cells which contain it. (Montreuil, et al).
•

• Regulation/Control
• Regulation and control of glycoproteins is not as straight forward as some might think.
"If someone was to understand regulation in glycoproteins he would have to look at the
enzymes that are involved in the biosynthesis pathway of these molecules; what is
affecting the enzyme activity (could be hormonal). The big interest in this area is in the
cloning of the genes, the cloning of the enzymes that are involved in the synthesis of the
oligosaccharide on the glycoproteins. Unfortunately, not that much is known on the
above subject" Dr. Roger Bretthauer
• On the other hand, control of glycoproteins can be seen through biosynthesis and
degradation. Here, the biosynthesis and degradation of the N-linked glycoproteins will be
emphasized.
• Synthesis
• The protein part of the glycoprotein is formed at the ribosomes, where all proteins are
synthesized, on template represented by RNA and DNA. As a result, its structure can
 change only through the mutation of the genetic material of the cell. On the other hand,
the carbohydrate component of a glycoprotein is not a product of the ribosome; it is
synthesized somewhere in the cytoplasm, but the exact site of synthesis has not yet been
established. Since it is not directly genetically controlled, the oligosaccharide part shows
a much greater variation (Scientific American).
• In contrast with O-linked glycoproteins, where oligosaccharide assemble occurs on the
polypeptide chain, N-linked glycoproteins assemble their oligosaccharide portions on a
lipid linked intermediate, dolichol phosphate. The first step in oligosaccharide synthesis
is the formation of that intermediate. In subsequent steps, sugars, the first being always
N-acetylglucosamine (GlcNAc), are chain-like connected to dolichol phosphate. One
more GlcNAc and three more mannose sugars are linked to the first GlcNAc to form the
typical core of N-linked glycoproteins. Addition of any other sugar can be in any possible
combination, according to the desired resulting functions. The specificity of the enzymes
is very important in the synthesis process. Every sugar added, is catalyzed by a different
enzyme. These group of enzymes are called glycosyltransferases (example Name). The
first addition of GlcNAc to dolichol phosphate is catalyzed by the specific enzyme
example) that cleave peptide bonds, and glycosidases (e.g example). enzymes that
remove sugars one at a time from the end of an oligosaccharide chain. Both of these
groups are contained in lysozomes. The lysosome attaches to a phagocyte, which has
engulfed a substance that needs to be broken down, and releases its enzymes in
it(Gottschalk). Next, these enzymes begin their catalytic action. In degradation, ad in
synthesis, the enzymes involved are very specific. After the glycoprotein is broken down,
its amino acid and sugar components are either metabolized or can be used in the
formation of another glycoprotein. Enzymatic degradation can provide much information
about the structure of the oligosaccharide chains, as well as about the carbohydrate
peptide linkage. For example, if a glycoprotein is treated with mannosidase (removes
mannose), and mannose is released, one can conclude that mannose residues were located
at the periphery of the molecule since glycosidases remove sugars from the end of the
oligosaccharide chain (Scientific American).
• Regulation and control is the organism's ultimate tool to monitor and adjust the
production or degradation of different molecules. Like a factory, it would be useless and
inefficient to produce excess products when there is no need for them. On the other hand,
shortage of products could be a problem too. Hopefully, further research will put some
light in the area of glycoprotein regulation.
• For a more detailed analysis on the biosynthesis and regulation of glycoproteins, the
reader is referred to one of the journal articles in the bibliography.
• Works Cited
• Personal communications. Bretthauer, Roger K. Professor of Biochemistry
Indiana University. interview at 11/28/95. Phone (219) 631-7348. Netscape :
[Link]

• Evans, Ronald M. "The steroid and Thyroid Hormone Receptor Superfamily." Science.
40 (1988): 889-894.
• Gottschalk, Alfred. Glycoproteins. Their Composition, Structure, and function. Elsevier
Publishing Company: New York, 1972.
• Herrera H., and E.M Rodriguez. "Secretory Glycoproteins of the Rat Subcommisoral
Organ Are N-Linked Complex-Type Glycoproteins. Demonstration by Combined Use of
Lectins and Specific Glycosidases, and by the Administration of Tunicamycin.
Histochemistry. 93 (1990): 607-615.
• Herscovics Annete, and Peter Orlean. "Glycoprotein Biosynthesis in Yeast." FASEB
Journal 7 (1993): 540-550.
• Ivatt, Raymond J. The Biology of Glycoproteins. Plenum Press: New York, 1984.
Kornfeld Rosaline, and Stuart Kornfeld. "Assembly of Asparagine-Linked
Oligosaccharide." Annual Review of Biochemistry 54 (1985): 631-664.
• Langan Thomas J., and Mary C. Slater. "Isoprenoids and Astroglial Cell Cycling:
Diminished Mevalonate Availability and Inhibition of Dolichol-Linked Glycoprotein
Synthesis Arrest Cycling Through Distinct Mechanisms". Journal of Cellular Physiology
149 (1991): 284- 292.
• Lennarz, William J. The Biochemistry of Glycoproteins and Proteoglycans. Plenum
Press: New York, 1980.
• Mathews, Christopher K., and K.E. van Holde. Biochemistry. The Benjamin/Cummings
Publishing Company, Inc.: Redwood City, 1990.
• Montreuil, J., Vliegenthart, J.F.G., and Schachter, H. Glycoproteins. Elsevier:
Amsterdam, 1995. Qiu Zhiyong, and Frank Tufaro and Shirley Gillam. "Brefeldin A and
Monensin Arrest Cell Surface Expression of Membrane Glycoproteins and Release of
Rubella Virus". Journal of General Virology 76 (1995): 885-863.
• Sharon, Nathan. Glycoproteins." Scientific American. May (1974): 78-86.
• Schulz, Georg E. And R.H. Schirmer. Principles of Protein Structure. Springer-Verlag:
New York, 1979.
• Zhu Xiaying, and Yucheng Zeng, and Mark A. Lehrman. "Evidence That the Hamster
Tunicamycin Resistence Gene Encodes UDP-GlcNac:Dolichol Phosphate N-
Acetylglucosamine-1-phosphate Transferase". The Journal of Biological Chemistry 267
(1992): 8895-8902.
•

• LINKS
• Glycoprotein Structure and Steroid Hormone Function
• Glycoproteins play an important part in hormone function. The action of hormones
depends on the initial binding of the hormone to a protein receptor molecule. In many
cases this molecule is a glycoprotein. Many hormones bind to receptors in the cell
membrane; these hormones never actually enter the cell. Steroids, on the other hand, bind
to an intracellular protein receptor. There is still controversy over whether the steroid
hormone receptor is found in the nucleus or the cytosol. However, it is clear that after the
steroid binds, the hormone-receptor complex moves to the nucleus. The hormone binding
domain of the receptor is found at the C-terminus. The amino acid sequence of this region
is highly diverse; it is not conserved from one protein to the next. Binding of the hormone
stimulates a conformational change in the hormone receptor. This change allows the
 hormone-receptor complex to bind to the DNA. The DNA binding domain is highly
conserved and is found within the central core of the protein. The central core contains a
very basic amino acid sequence. In the cellular environment, these bases will tend to pick
up a hydrogen and become positively charged. The positive charge will attract the
hormone-receptor complex to the negatively charged DNA. Binding of the complex to
the DNA stimulates transcription (Evans 890-891 and Mathews 808-809).
• Similarities Between Glycoproteins, Cytochromes, and
Metalloenzymes
• Cytochromes have features that are quite similar to transferrins, a particular class of
glycoproteins. First of all, cytochromes make up some of the integral proteins found in
membranes, as do glycoproteins. Second of all, the main function of cytochromes is the
binding of ion cations. Via oxidoreduction with these cations of 2+state, cytochromes
bind iron to a porphyrin prosthetic group, forming a heme group (Mathews). The function
is to transport cations in and out of the cell. Transferrin is an iron binding protein as well.
It interacts with iron cations of the 2+state which also bind to a porphyrin group,
Protoporphyrin IX, to form a heme group. Transferrins carry ions to many different
locations in the body including in and out of cells (Gottschalk). Another group of
molecules that serve a function related to glycoproteins are the metalloenzymes. These
enzymes, as their name implies, bind to metal ions via the same type of heme groups just
discussed (Gottschalk). One class of glycoprotein enzymes, the oxidoreductases, contain
an enzyme called chloroperoxidase. Like transferrin, chloroperoxidase contains
protophyrin IX and forms the heme group with iron 3+ (Mathews). Eicosanoids, are also
related to glycoproteins because they recognize the receptors on cells which are
glycoproteins.
• Inhibition of asparagine linked glycoproteins by antibiotics
• Synthesis of N-linked glycoproteins can be inhibited with the use of
antibiotics (function of antibiotics). Examples are monensin, mevinolin and
tunicamycin. Monensin, a monocovalent ionophore, inhibits the transport of
proteins through the endoplasmic reticulum- Golgi complex (general virology
855). Mevinolin on the other hand, is an inhibitor of mevalonate synthesis.
Mevalonate is the precursor of dolichol and other isoprenoid lipids (cellular
physiology 284). Finally, as mentioned above, asparagine linked glycosylation
involves the first step of addition of GlcNAc to dolichol diphosphate. This
reaction is catalyzed by the enzyme UDP-GlcNAc:dolichol phosphate N-
acetylglucosamine-1-phosphate transferase or GPT . Tunicamycin is a specific
inhibitor of GPT, therefore it can inhibit the synthesis of all N-linked
glycoproteins (biological chemistry 8895). To give just an example of the
effectiveness of tunicamycin, when it was injected to rats' hearts, it killed 12,
24, 50, and 60 h after the injection (histochemistry 607). Another connection
could be seen with the function of the ribosomes, since the polypeptide chain
of all glycoproteins is made there.

Warning: The NCBI web site requires JavaScript to function. more...

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Contents

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• Adhesion Molecules
○ Paramyxovirus Entry
○ Biological Roles of Prion Domains
○ The Role of Neuropilin in Vascular and Tumor Biology
○ Structural and Functional Relation of Neuropilins
○ Neuropilin and Its Ligands in Normal Lung and Cancer
○ Neuropilin and Class 3 Semaphorins in Nervous System Regeneration
• Aging
○ Yeast RecQ Helicases: Clues to DNA Repair, Genome Stability and
Aging
○ Sensory Influence on Homeostasis and Lifespan: Molecules and Circuits
○ Post-Translational Modification of Cellular Proteins by Ubiquitin and
Ubiquitin-Like Molecules: Role in Cellular Senescence and Ageing
• Angiogenesis
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
○ Vascular Endothelial Growth Factor in Malignant Disease of the Central
Nervous System
○ Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-
Endothelial Cells: Autocrine Signalling by VEGF
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
• Apoptosis
○ Autophagy in Caenorhabditis elegans
○ Apoptosis Dependent and Independent Functions of Caspases
○ The Role of Caspases in Modulation of Cytokines and Other Molecules
in Apoptosis and Inflammation
○ Caspases, Bcl-2 Family Proteins and Other Components of the Death
Machinery: Their Role in the Regulation of the Immune Response
 ○ Learning from Deficiency: Gene Targeting of Caspases
○ Caspase Activation in Cancer Therapy
○ Caspase-Independent Cell Death Mechanisms
○ Caspases as Targets for Drug Development
○ In Situ Activation of Caspases Revealed by Affinity Labeling Their
Enzymatic Sites
• Atherosclerosis
○ Antigen Recognition by γδ T-Cells
• Autoimmunity
○ Targeting Antigen-Specific T Cells for Gene Therapy of Autoimmune
Disease
○ Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-
Induced Arthritis
○ Cytokines in the Treatment and Prevention of Autoimmune Responses
○ Involvement of Cytokines in the Pathogenesis of Systemic Lupus
Erythematosus
○ Gene Therapy-Based Approach for Immune Tolerance Induction Using
Recombinant Immunoglobulin Carriers
○ Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune
Thrombocytopenic Purpura
○ Gastroenterologic and Hepatic Diseases
○ Inflammatory Myopathies: Dermatomyositis, Polymyositis and Inclusion
Body Myositis
○ Immunogene Therapy with Nonviral Vectors
○ Cytokines and Chemokines in Autoimmune Disease: An Overview
○ CTLA-4 in Type 1 Diabetes Mellitus
○ 4-1BB as a Therapeutic Target for Human Disease
• Bioinformatics
○ Prediction of Protein Function Two Basic Concepts and One Practical
Recipe
• Biomaterials
○ Regulation of Medical Devices
○ Tissue Engineering Constructs and Commercialization
• Biosurfactants
○ Screening Concepts for the Isolation of Biosurfactant Producing
Microorganisms
• Biotechnology
 ○ Use of piggyBac and a Sindbis Virus for Foreign Gene Expression and
RNAi in the Silkworm
○ Molecular Properties of Voltage-Gated Calcium Channels
○ Why Government Is the Problem (and What to Do about It)
○ Transgenic Analysis of the Biological Functions of a Doublesex
Homologue in Bombyx mori
○ Carbon Nanostructures as a New High-Performance Platform for MR
Molecular Imaging
○ Foundations of E-Cell Simulation Environment Architecture
○ Electrophysiological Simulation of Developmental Changes in Action
Potentials of Cardiomyocytes
○ Distributed Cell Biology Simulations with the E-Cell System
○ Bacterial Vectors for RNAi Delivery
○ HSV as a Vector in Vaccine Development and Gene Therapy
• Cancer Development
○ Epithelial-Mesenchymal Transitions in Human Cancer
• Cancer Genetics
○ Cellular Functions of Menin
• Cancer Metastasis
○ Integrins in Cancer Cell Invasion
○ The Plasminogen Activation System in Cell Invasion
○ Maspin: Functional Insights from a Structural Perspective
○ Maspin and Pericellular Plasminogen Activation in Cell-Matrix
Interaction
○ Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating
Integrin Expression and Function
○ The Role of Maspin in Tumor Progression and Normal Development
○ The Role of Maspin in Human Placental Development
○ Keratinocyte Interactions with Fibronectin during Wound Healing
• Cell Biology
○ Intracellular Membrane Fusion
○ The Golgi Apparatus
○ Clathrin-Mediated Endocytosis
○ Decoding the Signaling Mechanism of Toll-Like Receptor 4 Pathways in
Wild Type and Knockouts
○ Carrier Motility
○ The Exocytic Pathway and Development
 ○ Memory Th1/Th2 Cell Generation Controlled by Schnurri-2
○ The “O” Class: Crafting Clinical Care with FoxO Transcription Factors
○ FOXP Genes, Neural Development, Speech and Language Disorders
○ Regulation and Coordination of Intracellular Trafficking: An Overview
○ Overview of Intracellular Compartments and Trafficking Pathways
○ Sumoylation as a Signal for Polyubiquitylation and Proteasomal
Degradation
○ Studies on the Very Large G Protein–Coupled Receptor From Initial
Discovery to Determining Its Role in Sensorineural Deafness in Higher
Animals
○ Autosomal Lyonization of Replication Domains During Early Mammalian
Development
○ X Chromosome Inactivation and Embryonic Stem Cells
○ NOTCH SIGNALING AND THE DEVELOPING HAIR FOLLICLE
○ NOTCH SIGNALING AND THE GENERATION OF CELL DIVERSITY IN
DROSOPHILA NEUROBLAST LINEAGES
○ THE NEURAL BASIS OF SEMANTIC AND EPISODIC FORMS OF SELF-
KNOWLEDGE: Insights from Functional Neuroimaging
• Cell Cycle
○ The Restriction Point of the Cell Cycle
○ DNA Damage-Independent Checkpoints from Yeast to Man
○ The Regulation of p53 Growth Suppression
○ Functional Interactions Between BRCA1 and the Cell Cycle
○ The Evolution of CDK-Activating Kinases
○ CDK-Activating Kinases in Higher Plants
○ Activating Phosphorylation of Cyclin-Dependent Kinases in Budding
Yeast
• Cell Invasion
○ Matrix Metalloproteinases in Cancer Cell Invasion
• Cell Metabolism
○ Theory of Organelle Biogenesis: A Historical Perspective
○ Microfibril-Associated Glycoprotein-1 (MAGP-1) and Other Non-fibrillin
Macromolecules Which May Possess a Functional Association with the
10 nm Microfibrils
○ Synaptic Endosomes
○ Endocytosis of Receptor Tyrosine Kinases: Implications for Signal
Transduction by Growth Factors
○ Macroautophagy in Mammalian Cells
○ Plant Lipocalins
○ The Plasma Lipocalins α1-Acid Glycoprotein, Apolipoprotein D,
Apolipoprotein M and Complement Protein C8γ
○ Molecular Biology of the OXPHOS System
○ Bacterial Lipocalins: Origin, Structure, and Function
○ Chaperone-Mediated Autophagy
○ Regulation of Paracellular Transport across Tight Junctions by the Actin
Cytoskeleton
○ Entry into the Endoplasmic Reticulum: Protein Translocation, Folding
and Quality Control
○ Tight Junction Proteins and Cancer
○ Membrane Resealing Mediated by Lysosomal Exocytosis
○ Transcriptional Regulation of Keratin Gene Expression
○ Lysosomal Proteases: Revival of the Sleeping Beauty
○ Preprotein Translocation through the Sec Translocon in Bacteria
○ Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a
RELevant Role in Cancer
○ Nuclear Import of Agrobacterium T-DNA
○ Keratins As Targets in and Modulators of Liver Diseases
○ Retinol Binding Protein and Its Interaction with Transthyretin
○ Keratin Intermediate Filaments and Diseases of the Skin
○ Important Mammalian Respiratory Allergens Are Lipocalins
○ Lipocalin Receptors: Into the Spotlight
○ α1-Microglobulin
○ Lipocalins in Clinical Medicine
○ Lysosomal Storage Disorders
○ Lipocalins in Arthropoda: Diversification and Functional Explorations
○ Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Glycodelin: A Lipocalin with Diverse Glycoform-Dependent Actions
○ Nonsecretory, Regulated Exocytosis: A Multifarious Mechanism
Employed by Cells to Carry Out a Variety of Functions
○ Protein Misassembly: Macromolecular Crowding and Molecular
Chaperones
○ Molecular Interaction Network of the Hsp90 Chaperone System
○ The Synapsins and the Control of Neuroexocytosis
 ○ Hsp90 and Developmental Networks
○ A Common Binding Site for Actin-Binding Proteins on the Actin Surface
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Cell-Free Synthesis of Defined Protein Conjugates by Site-directed
Cotranslational Labeling
○ Reverse Engineering Models of Cell Cycle Regulation
○ Nuclear Import of Plant Proteins
○ Dynamic Connections of Nuclear Envelope Proteins to Chromatin and
the Nuclear Matrix
○ Nuclear Envelope Dynamics in Drosophila Pronuclear Formation and in
Embryos
○ Nuclear Envelope Breakdown and Reassembly in C. elegans:
Evolutionary Aspects of Lamina Structure and Function
○ Laminopathies: One Gene, Two Proteins, Five Diseases..
○ Dynamics of Nuclear Envelope Proteins During the Cell Cycle in
Mammalian Cells
○ Calnexin and Calreticulin, Molecular Chaperones of the Endoplasmic
Reticulum
○ Calreticulin-Mediated Nuclear Protein Export
○ Calreticulin and the Endoplasmic Reticulum in Plant Cell Biology
○ Calnexin and Calreticulin, ER Associated Modulators of Calcium
Transport in the ER
○ ER Calcium and ER Chaperones: New Players in Apoptosis?
○ Calreticulin in Cytotoxic Lymphocyte-Mediated Cytotoxicity
○ A Role for Calreticulin in the Clearance of Apoptotic Cells and in the
Innate Immune System
○ Calreticulin and Tumor Suppression
○ Cell Surface Calreticulin: Role in Signaling Thrombospondin Anti-
Adhesive Activity
○ Calreticulin Regulation of Lung Endothelial NOS Activity
• Channels and Transporters
○ Cell-Cell Fusion: Transient Channels Leading to Plasma Membrane
Merger
○ Anion Conduction by CFTR: Mechanisms and Models
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Voltage-Dependent Inactivation of Voltage Gated Calcium Channels
○ A Brief History of Calcium Channel Discovery
 ○ Block of Voltage-Gated Calcium Channels by Peptide Toxins
○ Calcium Channel Block and Inactivation: Insights from Structure-
Activity Studies
○ Ca2+ Chemistry, Storage and Transport in Biologic Systems: An
Overview
○ Hepatic Copper Transport
○ Drug-Induced Cholestatic Liver Disease
○ Cell-Cell Channels and Their Implications for Cell Theory
○ Cytoplasmic Bridges in Volvox and Its Relatives
○ Gap Junctions: Cell-Cell Channels in Animals
○ The Tetrahymena Conjugation Junction
○ Mating Cell-Cell Channels in Conjugating Bacteria
○ Fusome as a Cell-Cell Communication Channel of Drosophila Ovarian
Cyst
○ Channels across Endothelial Cells
○ Cytonemes as Cell-Cell Channels in Human Blood Cells
○ Vegetative Hyphal Fusion in Filamentous Fungi
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Genetics, Mutations, and Polymorphisms
○ Hepatocyte Transplantation and Liver-Directed Gene Therapy
○ Phylogeny of Major Intrinsic Proteins
• Chaperones
○ Nucleotide Exchange Factors for Hsp70 Molecular Chaperones
○ Functions of the Hsp90-Binding FKBP Immunophilins
• Circadian Rhythms
○ Circadian Organization in the Algal Flagellate Euglena
• Coagulation
○ Regulation of Tissue Factor Expression
○ Factor XI, TAFI and DIC
○ Cytokines as Regulators of Coagulation
○ DIC at the Intersection of the Thrombotic, Fibrinolytic and Inflammatory
Axes
○ Genetic Risk Factors for Disseminated Intravascular Coagulation
○ Endothelial Cell Perturbation and Disseminated Intravascular
Coagulation
 ○ Blood-Borne Tissue Factor (Including Microparticles)
• Cytokines/Growth Factors
○ IL-10 Gene Polymorphisms in Transplantation
○ The Structure of the Type 1 Insulin-Like Growth Factor Receptor
○ Interleukin-10 Gene Polymorphisms and Cancer
○ The Role of IL-10 in Autoimmune Pathology
• Development
○ Embryonic Salivary Gland Branching Morphogenesis
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Integrins and Development: Integrins in Skeletal Cell Function and
Development
○ Membrane Lipid Rafts and Their Role in Axon Guidance
○ Epithelial-Mesenchymal Transformation in the Embryonic Heart
○ GSK3-Signal Regulation of Pattern Formation in Dictyostelium: Wnt-
Like Pathways During Non-Canonical Multicellular Development
○ Functional and Ecological Effects of Isoform Variation in Insect Flight
Muscle
○ Change of Epithelial Fate: Lessons from Gastrulation in Drosophila
○ Cadherin-Mediated Cell-Cell Adhesion and the Microtubule Network
○ TGFβ-dependent Epithelial-Mesenchymal Transition
○ Branching Morphogenesis of the Prostate
○ Expression and Function of Pitx2 in Chick Heart Looping
○ Neural Crest and the Development of the Enteric Nervous System
○ Matrix Metalloproteases and Epithelial-to-Mesenchymal Transition:
Implications for Carcinoma Metastasis
○ Whole Genome Approaches to Studying Drosophila Muscle
Development
○ Muscle Morphogenesis: The Process of Embryonic Myoblast Fusion
○ Development of the Larval Somatic Musculature
○ The Pathophysiological Role of Impaired Calcium Handling in Muscular
Dystrophy
○ X-Ray Diffraction of Indirect Flight Muscle from Drosophila in Vivo
○ The Sarcoglycans
○ The Role of Insulin-like Growth Factors in the Epithelial to Mesenchymal
Transition
○ Epithelium–Mesenchyme Transitions Are Crucial Morphogenetic Events
Occurring During Early Development
○ How Is the Branching of Animal Blood Vessels Implemented?
○ Integrins and Associated Proteins in Drosophila Development
○ Roles for Integrins and Associated Proteins in the Haematopoietic
System
○ Development of the Cardiac Musculature
○ Shh/Gli Signaling During Murine Lung Development
○ New Perspectives in Shh Signalling?
○ Role of shh and Gli Signalling in Oligodendroglial Development
○ Branching Morphogenesis in Vertebrate Neurons
○ Sonic Hedgehog Signaling in the Developing and Regenerating Fins of
Zebrafish
○ Role of Hedgehog and Gli Signalling in Telencephalic Development
○ Structure and Function of the Dystrophin-Glycoprotein Complex
○ Caveolin-3 and Limb-Girdle Muscular Dystrophy
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Cranial Neural Crest and Development of the Head Skeleton
○ Mesoderm Formation in the Drosophila Embryo
○ Neural Crest Delamination and Migration: Integrating Regulations of
Cell Interactions, Locomotion, Survival and Fate
○ Insect Flight Muscle Chemomechanics
○ The Role of Integrins in Cell Migration
○ Neural Crest Cell Plasticity: Size Matters
○ Neural Crest Stem Cells
○ Integrins: An Overview of Structural and Functional Aspects
○ An Evolutionary Perspective on Eukaryotic Membrane Trafficking
○ Slits and Their Receptors
○ Origins and Evolution of Cotranslational Transport to the ER
○ Origins and Evolution of the Actin Cytoskeleton
○ Comparison of Muscle Development in Drosophila and Vertebrates
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
○ The Genetic Regulation of Pigment Cell Development
○ Origin and Evolution of Self-Consumption: Autophagy
○ The Contribution of the Neural Crest to the Vertebrate Body
○ Dorsoventral Patterning of the Brain: A Comparative Approach
 ○ VEGF and Endothelial Guidance in Angiogenic Sprouting
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ CtBP and Hematopoietic Transcriptional Regulators
○ A New Member of the CtBP/BARS Family from Plants: Angustifolia
○ Simulation of Human Erythrocyte Metabolism
○ A Model Library of Bacterial Chemotaxis on E-Cell System
○ CtBP3/BARS and Membrane Fission
○ Hsp70-Mediated Protein Refolding in E-Cell
○ VEGF Receptor Signalling in Vertebrate Development
○ Vascular and Nonvascular Roles of VEGF in Bone Development
○ Morphogenesis of Epithelial Appendages: Variations on Top of a
Common Theme and Implications in Regeneration
○ Wnt/Wingless Signaling in Drosophila
○ The Role of Wnt Signaling in Vertebrate Head Induction and the
Organizer-Gradient Model Dualism
○ The Wnt Gene Family and the Evolutionary Conservation of Wnt
Expression
○ Secreted Antagonists/Modulators of Wnt Signaling
○ Patterning the Vertebrate Neural Plate by Wnt Signaling
○ Wnt/Wg and Heart Development
○ Wnt Signaling and Cell Migration
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
• DNA Surveillance and Repair
○ Roles of Poly(ADP-Ribose) Metabolism in the Regulation of Centrosome
Duplication and in the Maintenance of Neuronal Integrity
○ PARP and the Release of Apoptosis-Inducing Factor from Mitochondria
○ DNA Damage Signaling through Poly(ADP-Ribose)
○ Dynamic Interaction between PARP-1, PCNA and p21waf1/cip1
○ Parp and Epigenetic Regulation
○ Genome Degradation by DNAS1L3 Endonuclease: A Key PARP-1-
Regulated Event in Apoptosis
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Role of Poly-ADP-Ribosylation in Cancer Development
○ The Fanconi Anemia/BRCA Pathway: FANCD2 at the Crossroad between
Repair and Checkpoint Responses to DNA Damage
 ○ Fluorescence-Signaling Nucleic Acid-Based Sensors
○ Trichothiodystrophy: A Disorder Highlighting the Crosstalk between
DNA Repair and Transcription
○ Mobile Genetic Elements of Malaria Vectors and Other Mosquitoes
○ Orchestration of Telomeres and DNA Repair Factors in Mammalian
Cells: Implications for Cancer and Ageing
○ Mechanisms of DNA Damage and Repair in Alzheimer Disease
○ Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks
in Mammalian Cells
• DNA Vaccines
○ The Introduction of New DNA Vaccines into Developing Countries
• Drug Design
○ A Conceptual Framework
○ Modeling Structure-Activity Relationships
○ Prediction of Drug-Like Properties
○ Evolutionary De Novo Design
○ Analysis of Chemical Space
• Endocrinology
○ Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated
Vesicle Exocytosis
○ Subcellular Compartmentalization of Insulin Signaling Processes and
GLUT4 Trafficking Events
○ Insulin Action in the Islet β-Cell
○ What Is Osteoporosis?
○ Insulin and IGF-I Receptor Structure and Binding Mechanism
○ Insulin Resistance
○ Insulin Action Gene Regulation
• Evolution
○ Ribozyme-Catalyzed Genetics
○ Origin and Evolution of DNA and DNA Replication Machineries
○ Life in a Tenuous Universe
○ The Frame for New Hypotheses of Evolution
○ Genomism and the Nature Trail
○ The Origin of Complexity
○ Our Young Planet: One Is Not a Choice
○ The Condensation of Life
 ○ The Origins of Species
○ Development of Biological Potential
○ Thoughts on Multi-Cellularity: How Nature Got Around Darwin
○ Natura non facit saltum (Nature does nothing in jumps)
○ The Invariance Concept
○ On the Evolution of Humans
○ Molecular Geneology
○ Experiments in Evolution
○ Quintessence
○ The Scope of Selection
• Extracellular Matrix
○ The Biogenesis and Cell Biology of Peroxisomes in Human Health and
Disease
○ Assembly of Microfibrils
• Gastroenterology
○ Nerve Regulation of Cholangiocyte Functions
○ Functional Heterogeneity of the Intrahepatic Biliary Epithelium
○ Bile Acid Interactions with Cholangiocytes
○ Estrogen Regulation of Cholangiocyte Proliferation
○ Nerve Regulation of Cholangiocyte Functions
○ Vascularization of the Intrahepatic Biliary Tree and Its Role in the
Regulation of Cholangiocyte Growth
○ Cytokine Regulation of Cholangiocyte Growth
○ Hyperemesis Gravidarum and Maternal Liver Disease
○ The Liver in Normal Pregnancy
○ Spectrum of Maternal Liver Disease
• Gene Expression
○ Stochastic Gene Expression: Dominance, Thresholds and Boundaries
○ Biological Consequences of Dosage Dependent Gene Regulation in
Multicellular Eukaryotes
○ GAGA: Structural Basis for Single Cys2His2 Zinc Finger-DNA Interaction
○ Identification of Mammalian E2F Regulatory Networks Using DNA
Microarray Hybridization Analyses
○ Homing Endonuclease I-TevI: An Atypical Zinc Finger with a Novel
Function
○ A Novel Test Statistic for the Identification of Local Selective Sweeps
Based on Microsatellite Gene Diversity
○ Periodic Selection and Ecological Diversity in Bacteria
○ LIM Domain and Its Binding to Target Proteins
○ MDM2: RING Finger Protein and Regulator of p53
○ Inferring Evolutionary History through Inter- and Intraspecific DNA
Sequence Comparison: The Drosophila janus and ocnus Genes
○ Selective Sweep in the Evolution of a New Sperm-Specific Gene in
Drosophila
○ The Superfamily of SCAN Domain Containing Zinc Finger Transcription
Factors
○ Putative Roles of kin17, a Mammalian Protein Binding Curved DNA, in
Transcription
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ A Zinc Ribbon Motif Is Essential for the Formation of Functional
Tetrameric Protein Kinase CK2
○ Rapid Evolution of Sex-related Genes: Sexual Conflict or Sex-specific
Adaptations?
○ Repression of Transcription by Curved DNA and Nucleoid Protein H-NS:
A Mode of Bacterial Gene Regulation
○ Curved DNA and Transcription in Eukaryotes
○ PNA and Oligonucleotide Inhibitors of Human Telomerase
○ Possible Roles of DNA Supercoiling in Transcription
○ MDM2: RING Finger Protein and Regulator of p53
○ Gene Regulatory Networks
○ Do DNA Triple Helices or Quadruplexes Have a Role in Transcription?
○ The Biology of Telomeres in Hypotrichous Ciliates
○ Scaling Laws in the Functional Content of Genomes: Fundamental
Constants of Evolution?
○ Regulation of Cardiomyocyte Proliferation and Apoptosis
○ Cell Cycle Reactivation in Skeletal Muscle and Other Terminally
Differentiated Cells
○ The Role of Unusual DNA Structures in Chromatin Organization for
Transcription
○ Molecular Mechanisms of Male Sex Determination: The Enigma of SRY
○ DNA: Alternative Conformations and Biology
○ Curved DNA and Prokaryotic Promoters: A Mechanism for Activation of
Transcription
○ Scale-Free Evolution: From Proteins to Organisms
 ○ Bioinformatics: Mystery, Astrology or Service Technology?
○ Extracting Information for Meaningful Function Inference Through Text-
Mining
○ Microarrays and Gene Regulation Networks in Yeast
○ Transcriptional Repression by the CtBP Corepressor in Drosophila
○ Structural Determinants of CtBP Function
○ Analytical Evolutionary Model for Protein Fold Occurrence in Genomes,
Accounting for the Effects of Gene Duplication, Deletion, Acquisition
and Selective Pressure
○ Power Law Correlations in DNA Sequences
○ Transcriptional Networks in Mammalian Gene Regulation
○ DNA Primer Extension by Telomerase
○ Transcriptional Profiling of the Hepatic Growth Response
○ Expression of Hox Genes in the Nervous System of Vertebrates
○ Telomeres: Guardians of Genomic Integrity or Double Agents of
Evolution?
○ Alternative Lengthening of Telomeres in Mammalian Cells
○ Evolution of Telomere Binding Proteins
○ Drosophila Telomeres: A Variation on the Telomerase Theme
○ Telomerase Activity as a Marker of Tumor Cell Survival to Evaluate
Sensitivity of Neoplastic Cells to Cancer Treatment
○ Myotonic Dystrophy: Discussion of Molecular Basis
○ Roles for TERT and Telomerase in Cell Differentiation and Apoptosis
○ Molecular Mechanisms of TRS Instability
○ Yeast Telomerases: Structure, Mechanisms and Regulation
○ The Significance of Quantitative Evaluation of Telomerase Activity and
hTERT mRNA Expression in Colorectal Cancers
○ Human, Mouse and Yeast Telomerase
○ Telomerase in Mesothelioma: Diagnostic and Therapeutic Applications
○ Telomerase Activity in Neuroblastomas: A New Molecular Marker for
Treatment Stratification and Prognostic Grouping
○ Telomerase and Radiosensitivity of Human Tumors
• Heart
○ Origin of Mechanotransduction: Stretch-Activated Ion Channels
○ Regional Differences and Variability in Left Ventricular Wall Motion
• Heat Shock Proteins
 ○ Assembly of Protein Aggregates in Neurodegeneration: Mechanisms
Linking the Ubiquitin/Proteasome Pathway and Chaperones
○ The Role of Heat Shock Proteins during Neurodegeneration in
Alzheimer's, Parkinson's and Huntington's Disease
• Hematology
○ Other Proteins and Their Interactions with FA Gene Products
○ The Genetic Basis of Fanconi Anemia
○ The FANCC Gene and Its Products
• Immunology
○ Animal Models of OXPHOS Disorders
○ Molecular Recognition of Haptens by T Cells: More Than One Way to
Tickle the Receptor
○ Phospholipases and Phagocytosis
○ IgA and Mucosal Homeostasis
○ Carbohydrate-Based Targets and Vehicles for Cancer and Infectious
Diseases Vaccines
○ Small GTP Binding Proteins and the Control of Phagocytic Uptake
○ Calcium Signaling During Phagocytosis
○ Regulation of Phagocytosis by FcγRIIb and Phosphatases
○ Adding Complexity to Phagocytic Signaling: Phagocytosis-Associated
Cell Responses and Phagocytic Efficiency
○ V(D)J Recombination: Of Mice and Sharks
○ Opioid Receptors on Peripheral Sensory Neurons
○ Morphological Correlates of Immune-Mediated Peripheral Opioid
Analgesia
○ Functional Evidence of Pain Control by the Immune System
○ Opioid Receptor Expression and Intracellular Signaling by Cells
Involved in Host Defense and Immunity
○ Experimental Evidence for Immunomodulatory Effects of Opioids
○ The Immune-Suppressive Effects of Pain
○ Lipoxins as an Immune-Escape Mechanism
○ Dynamic Aspects of TCRα Gene Recombination: Qualitative and
Quantitative Assessments of the TCRα Chain Repertoire in Man and
Mouse
○ Viral TNF Inhibitors as Potential Therapeutics
○ CD8 T-Cell Memory Differentiation during Acute and Chronic Viral
Infections
 ○ Chromatin Mechanisms Regulating Gene Expression In Health And
Disease
○ Earthworm Immunity
○ TRIM PROTEINS AS RING FINGER E3 UBIQUITIN LIGASES
○ REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for
Treatment of Mast-Cell Related Diseases?
○ GASTROPOD IMMUNOBIOLOGY
○ MAST CELLS AND IMMUNOREGULATION/IMMUNOMODULATION
• Infectious Disease
○ Everything (or Almost Everything) You Want to Know about Genetically
Modified Mosquitoes for Malaria Control but Are (Maybe) Afraid to Ask
○ Predicting the Spread of a Transgene in African Malaria Vector
Populations: Current Knowledge and Limitations
○ Invasion and Intracellular Survival by Toxoplasma
○ Negative Signaling and Modulation of Macrophage Function in
Trypanosoma cruzi Infection
○ Pro-Inflammatory Responses in Macrophages during Toxoplasma
gondii Infection
○ Avoidance of Innate Immune Mechanisms by the Protozoan Parasite,
Leishmania spp
○ Insect Population Suppression Using Engineered Insects
○ Current and Emerging Approaches to Studying Invasion in
Apicomplexan Parasites
• Ischemia-Reperfusion
○ Therapeutic Utilities of SOD Mimetics: Cancer, Radiotherapy and SOD
Mimetics
○ Development of Manganic Porphyrin Mimetics of Superoxide Dismutase
Activity
○ Role of Superoxide in Post-Ischemic Liver Injury
○ Evaluation of a Superoxide Dismutase Mimetic As an Adjunct to
Interleukin 2 Based Cancer Therapy
• Medical
○ STATs and Infection
○ JAK/STAT Pathway Signalling in Drosophila Melanogaster
○ Disease Transmission Models for Public Health Decision-Making:
Designing Intervention Strategies for Schistosoma japonicum
○ Parameter Estimation and Site-Specific Calibration of Disease
Transmission Models
• Molecular Biology
 ○ RNA Modification Subsystems in the SEED Database
○ KIR Genes and Their Role in Spondyloarthropathies
○ Antibiotic Resistance in Bacteria Caused by Modified Nucleosides in
23S Ribosomal RNA
○ The “PACE” Concept Pointed at New Key Proteins Involved in RNA
Metabolism
○ DNA Demethylation
○ Adhesion-Dependent Modulation of Macrophage K+ Channels
○ Pseudouridine Formation, the Most Common Transglycosylation in RNA
○ Folate-Dependent Thymidylate-Forming Enzymes: Parallels between
DNA and RNA Metabolic Enzymes and Evolutionary Implications
○ The Interplay between RNA and DNA Modifications: Back to the RNA
World
○ Deciphering the Complex Enzymatic Pathway for Biosynthesis of
Wyosine Derivatives in Anticodon of tRNAPhe
○ Nucleic Acids Are Not Boring Long Polymers of Only Four Types of
Nucleotides: A Guided Tour
○ Chemokine Binding Proteins Encoded by Pathogens
○ Boomerangs, Bananas and Blimps: Structure and Function of F-BAR
Domains in the Context of the BAR Domain Superfamily
○ Gas7
○ Enzyme-RNA Substrate Recognition in RNA-Modifying Enzymes
• Nanomedicine
○ STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?
• Neurodegenerative Disease
○ DSD-1-Proteoglycan/Phosphacan and Receptor Protein Tyrosine
Phosphatase-Beta Isoforms During Development and Regeneration of
Neural Tissues
○ Interleukin-10 and Psoriasis
○ Idiopathic Parkinson's Disease: Staging an α-Synucleinopathy with a
Predictable Pathoanatomy
○ Chromosome 1 and Other Hotspots for Parkinson's Disease Genes
○ Fibroblast Growth Factors
○ Neuronal Survival and Cell Death Signaling Pathways
○ Paved with Good Intentions: The Link between Cell Cycle and Cell
Death in the Mammalian Central Nervous System
○ α-Synuclein Physiology and Membrane Binding
○ Na Channels and Ca2+ Channels of the Cell Membrane as Targets of
Neuroprotective Substances
 ○ Heat Shock Proteins and Neuroprotection
○ Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain
Ischemia Following Delayed Intravenous Administration of
Neurotrophins
○ Neuroprotective Strategies in Animal and in Vitro Models of Neuronal
Damage: Ischemia and Stroke
○ Vascular Endothelial Growth Factor
○ Cell Cycle and Chromosome Segregation Defects in Alzheimer's
Disease
○ Neuroprotective Activity of Metabotropic Glutamate Receptor Ligands
○ Excitatory Amino Acid Neurotoxicity
○ Dopamine and Parkinson's Disease
○ Neurotrophins
○ Overview Αβ Metabolism: From Alzheimer Research to Brain Aging
Control
○ β-Secretase: Progress and Open Questions
○ APP α-Secretase, a Novel Target for Alzheimer Drug Therapy
○ γ-Secretase and Presenilin
○ Functional Roles of APP Secretases
○ Proteolytic Degradation of Αβ by Neprilysin and Other Peptidases
○ Αβ Degradation by Endothelin-Converting Enzymes
○ Ab Metabolism in Cholesterol-Enriched Membrane Microdomains
○ Amyloid β-Protein in Low-Density Membrane Domains
○ Transport-Clearance Hypothesis for Alzheimer's Disease and Potential
Therapeutic Implications
○ Potential Role of Endogenous and Exogenous Ab Binding Molecules in
Ab Clearance and Metabolism
○ Modulating Amyloid β Levels by Immunotherapy: A Potential
Therapeutic Strategy for the Prevention and Treatment of Alzheimer's
Disease
• Neuropharmacology
○ Diurnal 5-HT Production and Melatonin Formation
○ Pineal Gland and Cancer—An Epigenetic Approach to the Control of
Malignancy: Evaluation of the Role of Melatonin
○ Cell Adhesion Molecules
○ Risks of Chronic Hypnotic Use
○ Sleep Hippocampal Theta Rhythm and Sensory Processing
○ Cannabinoid Receptors and Signal Transduction
 ○ Protein Kinase A
○ A Comparison of Visual Analog Scale and Categorical Ratings in
Assessing the Patient's Estimate of Sleep Quality
• Neuroscience
○ Role of Semaphorins during Axon Growth and Guidance
• Nucleus
○ Riboflavin and Methylenetetrahydrofolate Reductase
○ Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR)
and Overview of Mutations/Polymorphisms
○ Methylenetetrahydrofolate Reductase Polymorphisms:
Pharmacogenetic Effects
○ Assays for Methylenetetrahydrofolate Reductase Polymorphisms
• Oncogenes
○ p53's Dilemma in Transcription: Analysis by Microarrays
○ TP63, TP73: The Guardian's Elder Brothers
○ Modes of p53 Interactions with DNA in the Chromatin Context
• Oncology
○ Fever, Pyrogens and Cancer
○ Gene Expression Profiling in Malignant Lymphomas
○ Cytoreduction, Peritonectomy and Hyperthermic Antiblastic Peritoneal
Perfusion for the Treatment of Peritoneal Carcinomatosis
○ Hyperthermic Isolated Limb Perfusion
○ Intracavitary Hyperthermic Perfusion
○ Locoregional Hyperthermia
○ Transcription of rDNA in the Yeast Saccharomyces cerevisiae
○ Pre-Ribosomal RNA Processing in Multicellular Organisms
○ PDGF Pathways and Growth of Basal Cell and Squamous Cell
Carcinomas
○ Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A
Radiation
○ Influence of Tumor Microenvironment on Thermoresponse: Biologic and
Clinical Implications
○ Physical Background and Technical Realizations of Hyperthermia
○ Effects of Local and Whole Body Hyperthermia on Immunity
○ Thermo-Chemo-Radiotherapy Association: Biological Rationale,
Preliminary Observations on Its Use on Malignant Brain Tumors
○ Molecular Mechanisms of ErbB2-Mediated Breast Cancer
Chemoresistance
 ○ Future Perspectives of Interstitial and Perfusional Hyperthermia
○ Roles of Multidrug Resistance Genes in Breast Cancer Chemoresistance
○ Insulin-Like Growth Factors and Breast Cancer Therapy
○ Novel Approaches for Chemosensitization of Breast Cancer Cells: The
E1A Story
○ Whole Body Hyperthermia at 43.5-44°C: Dreams or Reality?
○ Overview of Resistance to Systemic Therapy in Patients with Breast
Cancer
○ Microarrays for Cancer Diagnosis and Classification
○ Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines:
Clinical Results
○ Cellular Interactions in Nasopharyngeal Carcinomas
• Protein
○ Structure, Function and Assembly of Flagellar Axial Proteins
○ Implications of 3D Domain Swapping for Protein Folding, Misfolding and
Function
○ From Artificial Antibodies to Nanosprings:The Biophysical Properties of
Repeat Proteins
○ The Budding Yeast PCH/F-BAR Proteins
○ Gas7
○ The Coronin Family of Proteins
○ Diversity of WD-repeat Proteins
○ A Brief History of the Coronin Family
○ Phylogenetic, Structural and Functional Relationships between WD-and
Kelch-Repeat Proteins
○ The Role of Mammalian Coronins in Development and Disease
○ Invertebrate Coronins
○ Evolutionary and Functional Diversity of Coronin Proteins
○ Coronin: The Double-Edged Sword of Actin Dynamics
○ Coronin 1 in Innate Immunity
○ Molecular Phylogeny and Evolution of the Coronin Gene Family
○ Coronin Structure and Implications
○ Nuclear APC
○ Role of Mammalian Coronin 7 in the Biosynthetic Pathway
○ Post-Targeting Functions of Signal Peptides
• Reproductive Biology
 ○ Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor
Functions during Epidermal Development and Disease
○ Bi-Directional Cell Trafficking During Pregnancy: Long-term
Consequences for Human Health
○ Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular
Immunity
○ The Role of Corticotropin-Releasing Hormone (CRH) on Implantation
and Immunotolerance of the Fetus
○ Characterization of Human Dendritic Cells at the Maternal-Fetal
Interphase
○ Important Role of Shh Controlling Gli3 Functions During the Dorsal-
Ventral Patterning of the Telencephalon
○ Spatial and Temporal Regulation of Hair Follicle Progenitors by
Hedgehog Signalling
○ MHC Molecules of the Preimplantation Embryo and Trophoblast
○ The Role of Regulatory T Cells in Materno-Fetal Tolerance
○ Cytogenetics of Human Sperm
○ Preimplantation Genetic Diagnosis (PGD): Screening for Aneuploidy in
Human Oocytes and Polar Bodies
○ Proteases and Their Cognate Inhibitors of the Serine and
Metalloprotease Subclasses, in Testicular Physiology
○ Antioxidant Systems and Oxidative Stress in the Testes
• RNA
○ Protein-Switched Ribozymes
○ Proteins Carrying One or More Unnatural Amino Acids
○ Therapies of Nonsense-Associated Diseases
○ All Termination Events Are Not Equal: Premature Termination in Yeast
Is Aberrant and Triggers NMD
○ Role of SMG-1-mediated Phosphorylation of Upf1 in NMD
○ NMD in Drosophila: A Snapshot into the Evolution of a Conserved
mRNA Surveillance Pathway
○ The snoRNPs and Related Machines: Ancient Devices That Mediate
Maturation of rRNA and Other RNAs
○ Trytophanyl-tRNA Synthetases
○ Tyrosyl-tRNA Synthetases
○ Cytokines, Chemokines and Their Receptors
○ Valyl-tRNA Synthetases
○ Protein-Induced RNA Switches in Nature
○ Class I Lysyl-tRNA Synthetases
 ○ Glutaminyl-tRNA Synthetases
○ Asparaginyl-tRNA Synthetases
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Aminoacyl-tRNA Synthetases and Disease
○ Human Upf Proteins in NMD
○ Phenylalanyl-tRNA Synthetases
○ Regulation of Gene Expression by Coupling of Alternative Splicing and
NMD
○ NMD and Human Disease
○ Polyadenylation and Degradation of RNA in Prokaryotes
○ Regulation of the Expression of Aminoacyl-tRNA Synthetases and
Translation Factors
○ Conformational Dynamics within the Ribosome
○ Tests of a Stereochemical Genetic Code
○ Evasion of Phagosome Lysosome Fusion and Establishment of a
Replicative Organelle by the Intracellular Pathogen Legionella
pneumophila
○ The End in Sight: Poly(A), Translation and mRNA Stability in Eukaryotes
○ Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized
for Gene Expression
○ Mechanism of Translation Initiation in Eukaryotes
○ A Prelude to Translational (Re)Initiation
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Mitochondrial Aminoacyl-tRNA Synthetases
○ Transfer RNA Structure and Identity
○ Post-Transcriptional Gene Silencing in Plants
○ Turnover of Mature miRNAs and siRNAs in Plants and Algae
○ miRNAs need a Trim Regulation of miRNA Activity by Trim-NHL Proteins
○ Structural Components and Architectures of RNA Exosomes
○ C. ELEGANS STAR PROTEINS, GLD-1 AND ASD-2, REGULATE SPECIFIC
RNA TARGETS TO CONTROL DEVELOPMENT
• Signal Transduction
○ Genetic Susceptibility to Infectious Diseases Linked to NRAMP1 Gene in
Farm Animals
○ FasL-Independent Activation of Fas
○ Plant Metal Transporters with Homology to Proteins of the NRAMP
Family
○ Regulation of Bacterial MntH Genes
○ Physiological Roles and Mechanisms of Signaling by TRAF2 and TRAF5
○ Metal-ion Transporters— From Yeast to Human Diseases
○ The Function of Toll-Like Receptors
○ Regulation of the RhoGTPases by RhoGDI
○ How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-
GLI Signaling as Anti-Cancer Therapy?
○ Rho Family GTPases and Cellular Transformation
○ GLI Genes and Their Targets in Epidermal Development and Disease
○ Regulation of Cell Motility by Abl Family Kinases
○ The Patched Receptor: Switching On/Off the Hedgehog Signaling
Pathway
○ Shh Expression in Pulmonary Injury and Disease
○ Regulation of Cell Adhesion Responses by Abl Family Kinases
○ Abl Family Kinases in Mammalian Development
○ Abl and Cell Death
○ Mechanisms of Activation of Abl Family Kinases
○ Regulation of Cytoskeletal Dynamics and Cell Morphogenesis by Abl
Family Kinases
○ TRAFs in RANK Signaling
○ Abelson Family Protein Tyrosine Kinases and the Formation of Neuronal
Connectivity
○ The LTβR Signaling Pathway
○ Neurons, Neurotrophins and Ceramide Signaling: Do Domains and
Pores Contribute to the Dichotomy?
○ The Role of Serine/Threonine Protein Phosphatases in Ceramide
Signaling
○ Chaperone Effects on Prion and Nonprion Aggregates
○ Insights into the Modulation of Ceramide Metabolism by Naturally
Occurring and Synthetic Sphingolipid Analogs as Monitored by
Electrospray Tandem Mass Spectrometry
○ Ceramide Glycosylation and Chemotherapy Resistance
○ S-Modulin
○ Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by
Divalent Cations and Polyamines
 ○ Target Recognition of Guanylate Cyclase by Guanylate Cyclase-
Activating Proteins
○ Centrins, a Novel Group of Ca2+-Binding Proteins in Vertebrate
Photoreceptor Cells
○ The TRP Calcium Channel and Retinal Degeneration
○ Ca2+-dependent Control of Rhodopsin Phosphorylation: Recoverin and
Rhodopsin Kinase
○ The Complex of cGMP-gated Channel and Na/Ca2+, K Exchanger in Rod
Photoreceptors
○ RGS9-1 Phosphorylation and Ca2+
○ Ceramide in the Regulation of Neuronal Development: Two Faces of a
Lipid
○ Therapeutic Implications of Ceramide-Regulated Signaling Cascades
○ Photoreceptor Degeneration and Ca2+ Influx through Light-Activated
Channels of Drosophila
○ Regulation of the Rod Photoreceptor Cyclic Nucleotide-Gated Channel
○ Mouse Models to Study GCAP Functions in Intact Photoreceptors
○ Using Mutant Mice to Study the Role of Voltage-Gated Calcium
Channels in the Retina
○ Calcium Channels at the Photoreceptor Synapse
○ Biosynthesis of Sphingolipids in Plants (and Some of Their Functions)
○ Ceramide 1-Phosphate in Cell Survival and Inflammatory Signaling
• Stem Cells
○ Knockout Mouse Models of Cytokine Action in Hematopoietic Stem Cell
Regulation
○ Cytokines, Receptors and Signalling Pathways Involved in Macrophage
and Dendritic Cell Development
• Tissue Engineering
○ Scleroderma Lung Fibroblasts: Contractility and Connective Tissue
Growth Factor
○ Repair of Osteochondral Lesions
○ Regulatory Issues: Down to the Bare Bones
○ Anatomy and Physiology of the Spinal Cord
○ Encouraging Regeneration of Host Neurones: The Use of Peripheral
Nerve Bridges, Glial Cells or Biomaterials
○ Replacement of Specific Neuronal Populations in the Spinal Cord
○ Replacement of Specific Populations of Cells: Glial Cell Transplantation
into the Spinal Cord
 ○ In Vitro Endothelialization: Its Contribution Towards an Ideal Vascular
Replacement
○ Biocompatibility of Polyurethanes
○ Tissue Repair in Asthma: The Origin of Airway Subepithelial Fibroblasts
and Myofibroblasts
○ Functional Assessment of Fibroblast Heterogeneity by the Cell-Surface
Glycoprotein Thy-1
○ Pro-Invasive Molecular Cross-Signaling between Cancer Cells and
Myofibroblasts
○ Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinase and
Matrix Turnover and the Fate of Hepatic Stellate Cells
• Transplant
○ Polyomavirus Allograft Nephropathy: Clinico-Pathological Correlations
○ Metabolic Management
• Vaccines
○ Immune Responses to DNA Vaccines: Induction of CD8 T Cells
○ Neisseria meningitidis Vaccines
○ DNA Vaccines against Bacterial Pathogens
○ Dendritic Cells: Important Adjuvants During DNA Vaccination
• Viruses
○ A Role for Chemokine Activity in Alphavirus Pathogenesis: Evidence
from the Analysis of Polyarthritis and Myalgia Post-Ross River Virus
Infection
○ Evolutionary Aspects of Human Endogenous Retroviral Sequences
(HERVs) and Disease
○ Structure and Replication of Hepatitis Delta Virus RNA
○ Hepatitis Delta Virus RNA Editing
○ Hepatitis Delta Antigen and RNA Polymerase II
○ Transforming Activities of JC Virus Early Proteins
○ DNA Packaging by Bacteriophage P22
○ Regulation of T Cell Immunity by OX40 and OX40L
○ BK Virus, JC Virus and Simian Virus 40 Infection in Humans, and
Association with Human Tumors
○ The ø29 DNA Packaging Motor: Seeking the Mechanism
○ Phylogenomics and Molecular Evolution of Polyomaviruses
○ Urine Cytology Findings of Polyomavirus Infections
○ Immunity and Autoimmunity Induced by Polyomaviruses: Clinical,
Experimental and Theoretical Aspects
 ○ Soluble Chemokine Binding Proteins Encoded by Viruses
○ Bacteriophage Lambda Terminase and the Mechanism of Viral DNA
Packaging
○ DNA Packaging in Bacteriophage T4
○ Bacteriophage SPP1 DNA Packaging
○ Polyomavirus-associated Nephropathy in Renal Transplantation: Critical
Issues of Screening and Management
○ Entry of Herpesviruses into Cells: The Enigma Variations
< PrevNext >

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.
Bookshelf ID: NBK6193

Structure and Function of the Dystrophin-Glycoprotein

Complex
James M. Ervasti.
Introduction
Go to:

• Top▲
Duchenne muscular dystrophy (DMD) is the most prevalent and severe form of human muscular
dystrophy. While clinical descriptions of DMD date back to the 1850's, over 100 years passed
before evidence suggested that the muscle cell plasma membrane, or sarcolemma, is
compromised in DMD muscle. The molecular basis for DMD and its associated sarcolemmal
instability became more clear with landmark studies published in the mid-to-late 1980's which
identified the gene defective in DMD.1 The DMD locus spans over 2.5 million bases
distinguishing it as the largest gene in the human genome. The array of transcripts expressed
from the DMD gene is complex due to the presence of multiple promoters and alternative
splicing. The largest transcripts encode a four-domain protein with a predicted molecular weight
of 427,000, named dystrophin. Dystrophin is the predominant DMD transcript expressed in
striated muscle and DMD gene mutations, deletions or duplications most frequently result in a
loss of dystrophin expression in muscle of patients afflicted with DMD. Based on its localization
to the cytoplasmic face of the sarcolemma and sequence similarity with domains/motifs common
to proteins of the actin-based cytoskeleton, dystrophin was hypothesized early on to play a
structural role in anchoring the sarcolemma to the underlying cytoskeleton and protect the
sarcolemma against stress imposed during muscle contraction or stretch. Biochemical studies
aimed at confirming the hypothesized structure and function of dystrophin revealed its tight
association with a multi-subunit complex, the so-named dystrophin-glycoprotein complex. Since
its description, the dystrophin-glycoprotein complex has emerged as an important structural unit
of muscle and also as a critical nexus for understanding muscular dystrophies arising from
defects in several distinct genes.
Initial Isolation and Characterization of the Dystrophin-
Glycoprotein Complex
Go to:

• Top▲
Following close behind the identification of dystrophin as the protein missing from DMD
muscle, the laboratory of Kevin Campbell demonstrated that dystrophin could be solubilized
from the membrane vesicle fraction of skeletal muscle homogenates using the detergent digitonin
and dramatically enriched by wheat germ agglutinin chromatography.2 Given that the primary
sequence contained no hydrophobic stretches to directly anchor dystrophin within the
sarcolemma, it seemed most likely that dystrophin indirectly bound to wheat germ agglutinin
through association with a membrane glycoprotein embedded in the sarcolemma and this idea
was confirmed by experiments showing that dystrophin binding to wheat germ agglutinin was
disrupted by chaotropic agents.2 While anion-exchange chromatography further amplified and
purified dystrophin over wheat germ agglutinin chromatography alone, numerous proteins
remained in the peak dystrophin fractions and lectin blotting minimally revealed 12 copurifying
glycoproteins as potential molecular partners for dystrophin.2 Sucrose gradient centrifugation
further resolved potential candidates to 9 proteins stained by Coomassie blue that were shown to
strictly cosediment with dystrophin (Fig. 1): a singlet of 88,000, a triplet of 59,000, a singlet of
50,000, a doublet of 43,000, a singlet of 35,000 (but present at a molar ratio of ˜2:1 relative to
dystrophin) and a singlet of 25,000 apparent Mr. Lectin blotting identified the 50,000, 43,000 and
35,000 species as glycoproteins and further revealed a broad band with an apparent molecular
weight of 156,000.3 While the 156,000 Mr protein was poorly stained by Coomassie blue, its
strong staining by wheat germ agglutinin and strict cosedimentation with dystrophin nonetheless
elevated its candidacy as a sarcolemmal glycoprotein receptor for dystrophin.3 Thus, the list of
potential dystrophin-associated proteins was narrowed down to 10 distinct Mr proteins, 5 of
which were glycosylated.

Figure 1
Protein Constituents of the Dystrophin-Glycoprotein Complex. Shown on the left is a Coomassie
blue-stained SDS-polyacrylamide gel loaded with dystrophin-glycoprotein complex purified
from rabbit skeletal muscle. Molecular weight standards are indicated (more...)
Protein Constituents of the Dystrophin-Glycoprotein Complex. Shown on the left is a Coomassie
blue-stained SDS-polyacrylamide gel loaded with dystrophin-glycoprotein complex purified
from rabbit skeletal muscle. Molecular weight standards are indicated on the left while the
molecular weights of each dystrophin-associated protein (DAP) or glycoprotein (DAG) are
indicated on the right. Also shown are western blots containing electrophoretically-resolved
dystrophin-glycoprotein complex that was enriched from digitonin-solubilized mouse skeletal
muscle by wheat germ agglutinin chromatography. Western blots were stained with antibodies
specific for dystrophin (DYS), α- and β-dystroglycan (DG), α-dystrobrevin (α-Db), syntrophin
(SYN), α-, β-, γ- and δ-sarcoglycans (SG) and sarcospan (SPN).
Importantly, the Campbell lab was simultaneously pursuing a long-term project aimed at
generating new monoclonal antibodies to calcium channels expressed in muscle. Since several
calcium channel subunits were known to be glycosylated, wheat germ agglutinin-enriched
fractions from detergent solubilized muscle membranes were used to immunize mice and screen
hybridomas. Screening positive clones against dystrophin-enriched preparations yielded
monoclonal antibodies to dystrophin, the 156,000 and 50,000 Mr dystrophin associated
glycoproteins. 3 The new antibodies were instrumental in confirming through
coimmunoprecipitation experiments the tight association of proteins that cosedimented with
dystrophin as well as their colocalization with dystrophin at the sarcolemma.3-5 Moreover, the
monoclonal antibodies were critical in demonstrating that the abundance of the 156,000 and
50,000 Mr dystrophin-associated glycoproteins was dramatically reduced in DMD muscle.3,6,7
Since these proteins colocalized with dystrophin in situ, copurified with dystrophin in
stoichiometric amounts even after several distinct protein purification methodologies, and were
diminished in dystrophin-deficient muscle, it was concluded that dystrophin was part of a large,
hetero-oligomeric complex that may serve to stabilize the sarcolemma. Because several
constituents were glycosylated and exploitation of this characteristic was so important in their
isolation, the assembly of proteins associated with dystrophin was named the dystrophin-
glycoprotein complex.
Additional biochemical analyses identified the 156,000 glycoprotein and 59,000 Mr triplet as
peripheral membrane proteins5 while the 50,000, 43,000, 35,000 and 25,000 Mr species behaved
as a subcomplex of integral membrane proteins.5,8 Based on its extensive glycosylation5,9 and
peripheral membrane association, the 156,000 Mr dystrophin-associated glycoprotein was
hypothesized to reside on the extracellular face of the sarcolemma and possibly function as a
receptor for a component of the extracellular matrix. These hypotheses were born out with the
cloning/sequencing of the gene encoding the 156,000 dystrophin-associated glycoprotein, which
is expressed from a single transcript along with one of the 43,000 Mr dystrophin-associated
glycoproteins.6 The propeptide is proteolytically processed into a wholly extracellular 156,000
subunit and a 43,000 Mr single-pass transmembrane subunit. Based on its extensive
glycosylation and association with dystrophin, the 156,000 and 43,000 Mr subunits were
renamed α- and β-dystroglycan, respectively. A screen of known extracellular matrix molecules
for skeletal muscle α-dystroglycan binding activity identified laminin as the first extracellular
ligand for α-dystroglycan.6,9 Laminin-Sepharose pull-down of the entire dystrophin complex
definitively demonstrated that α-dystroglycan was a stoichiometric component of the complex.9
These results also led to the hypothesis that the dystrophin-glycoprotein complex may play a role
in muscle cell adhesion to the basal lamina.
Working independently, Ozawa and colleagues corroborated10-12 many of the key findings first
reported by the Campbell laboratory and they made some important original contributions in
elucidating several of the protein-protein interactions within the complex (discussed below).
However, Ozawa and colleagues strongly disputed two important conclusions of Campbell's
group. First, they initially dismissed α-dystroglycan as an important component of the
dystrophin-glycoprotein complex because it could not be stained by Coomassie blue.13 Ozawa
and colleagues also strongly contested the initial identification of the 59,000 Mr α-
dystrobrevin/syntrophin triplet as cytoplasmic peripheral membrane proteins because their
experiments led them to conclude that one of the proteins was a transmembrane glycoprotein. 12
In subsequent work,14 it is clear that Ozawa and colleagues ultimately concurred that α-
dystroglycan is an important component of the complex and that syntrophins are nonglycosylated
cytoplasmic proteins. Using limited proteolysis, wheat germ agglutinin chromatography and an
array of site-specific antibodies, Ozawa and colleagues first demonstrated that the cysteine-rich
and first half of the C-terminal domains of dystrophin were important for its binding to the
glycoprotein complex.11 By blot overlay assay, they showed that β-dystroglycan, and the 88,000
and 59,000 Mr dystrophin-associated proteins (α-dystrobrevins and syntrophins) directly bound
the cysteine-rich and/or C-terminal domains of dystrophin,15 despite failing to reconcile their
prior crosslinking studies where they concluded that the 50,000 and 35,000 Mr dystrophin-
associated glycoproteins were directly associated with dystrophin and most important in
anchoring it to the sarcolemma.10 Ozawa and colleagues also more conclusively showed16 that the
dystrophin-glycoprotein complex could be dissociated into 3 sub-complexes consisting of α- and
β-dystroglycan (dystroglycan complex), the 50,000, 43,000, and 35,000 Mr dystrophin-associated
glycoproteins (sarcoglycan complex), dystrophin plus the 87,000 and 59,000 Mr dystrophin-
associated proteins (dystrophin/dystrobrevin/syntrophin complex). However, it bears noting that
several studies predating the work of Ozawa and colleagues reported data suggesting resolution
of sub-complexes with similar molecular compositions. 5,8,17,18
The largely biochemical studies described above suggested that the dystrophin-glycoprotein
complex may function to physically couple the sarcolemmal cytoskeleton with the extracellular
matrix (Fig. 2) and that loss of this structural linkage may render the sarcolemma more
susceptible to damage when exposed to mechanical stress. The purified dystrophin-glycoprotein
complex also provided a substrate for peptide sequencing and antibody production which yielded
new probes important in the identification of genes encoding all dystrophin associated teins and
elucidation of their respective roles in Duchenne and other forms of muscular dystrophy.
Notably, the genes encoding several dystrophin-associated proteins cause forms of muscular
dystrophy when mutated in humans or when knocked out in mice. Since dystrophin and its
associated proteins are each a story in and of themselves, I will leave their detailed discussions to
be elaborated in the specific chapters that follow. Below I will summarize the large body of
evidence supporting an important mechanical role for the dystrophin-glycoprotein complex and
then discuss its function within the larger protein network of skeletal muscle. Finally, I will
propose an engineering design analogy that I believe best fits existing data.

Figure 2
Model of the Dystrophin-Glycoprotein Complex. Dystrophin is thought to physically couple the
sarcolemma with the costameric cytoskeleton (see Fig. 3) through lateral association of its N-
terminal and rod domains with cytoplasmic γ-actin filaments (more...)
Model of the Dystrophin-Glycoprotein Complex. Dystrophin is thought to physically couple the
sarcolemma with the costameric cytoskeleton (see Fig. 3) through lateral association of its N-
terminal and rod domains with cytoplasmic γ-actin filaments and through direct binding of its
cysteine-rich domain to the β-subunit of the dystroglycan complex. Oligosaccharides present on
α-dystroglycan are important for its binding to laminin-2 of the extracellular matrix. The
sarcoglycan-sarcospan complex is thought to strengthen the noncovalent binding of dystrophin
and α-dystroglycan with β-dystroglycan. α-Dystrobrevin appears to couple dystrophin with the
sarcoglycan-sarcospan complex and also link the dystrophin-glycoprotein complex with the
intermediate filament cytoskeleton (see Fig. 4). Two syntrophin molecules are anchored through
homologous binding sites present in the C-terminal domains of dystrophin and α-dystrobrevin.
Syntrophins are thought to serve as adaptor molecules that localize signaling molecules near the
sarcolemma (see Fig. 4). Redrawn from.95
In Support of a Mechanical Function for the Dystrophin-
Glycoprotein Complex
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Within skeletal myofibers, dystrophin is enriched in a discrete, rib-like lattice termed
costameres.19,20 Costameres are protein assemblies that circumferentially align in register with the
Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the
sarcolemma in striated muscle cells (Fig. 3). A variety of data indicate that costameres are a
striated muscle-specific elaboration of the focal adhesions expressed by nonmuscle cells.21
Classical experiments by Street22 and the Sangers23 suggest that costameres function to laterally
transmit contractile forces from sarcomeres across the sarcolemma to the extracellular matrix and
ultimately to neighboring muscle cells. Lateral transmission of contractile force would be useful
for maintaining uniform sarcomere length between adjacent actively contracting and resting
muscle cells comprising different motor units within a skeletal muscle. It is also logical that the
sites of lateral force transmission across the sarcolemma would be mechanically fortified to
minimize stress imposed on the relatively labile lipid bilayer. Other results suggest that
costameres may also coordinate an organized folding, or “festooning” of the sarcolemma,22,24
which again may minimize stress experienced by the sarcolemmal bilayer during forceful muscle
contraction or stretch. Thus, in support of its hypothesized mechanical function, dystrophin is
enriched within a structure (the costamere) that likely transmits mechanical force to and through
the sarcolemma.

Figure 3
The costameric cytoskeleton of striated muscle. Dystrophin is enriched at costameres, protein
assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and
physically couple force-generating sarcomeres with the sarcolemma. (more...)
The costameric cytoskeleton of striated muscle. Dystrophin is enriched at costameres, protein
assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and
physically couple force-generating sarcomeres with the sarcolemma. Redrawn from 21
Consistent with its enrichment at costameres in normal muscle, the absence of dystrophin in
humans and mice leads to a disorganized costameric lattice.19,25-28 Extensive data consistently
report that the dystrophin-deficient sarcolemma is exceedingly fragile29-31 resulting in
dramatically increased movement of membrane impermeant molecules across the sarcolemma of
dystrophin-deficient muscle.30-42 Both necrosis and sarcolemmal permeability of dystrophin-
deficient muscle are exacerbated by physical exercise and improved by muscle immobilization.
33,35,39,42-45
Physiological studies have demonstrated that force production by dystrophin-deficient
muscle is significantly decreased when normalized against muscle cross-sectional area.40,41,46-59
Interestingly, force output by dystrophin-deficient muscle is hypersensitive to lengthening, or
eccentric contraction60,61 and the force decrement exhibited by dystrophin-deficient muscle
undergoing eccentric contraction positively correlates with acutely increased sarcolemmal
permeability.40,41,53-55,59-63 Immunofluorescence analysis of mechanically peeled sarcolemma has
demonstrated that dystrophin at costameres is tightly attached to the sarcolemma20 and its
presence is necessary for strong coupling between the sarcolemma and costameric actin
filaments comprised of cytoplasmic γ-actin.64 Transgenic overexpression of the dystrophin
homologue utrophin, or a dystrophin construct retaining the β-dystroglycan binding site and one
actin binding domain is sufficient to restore coupling between the sarcolemma and costameric
actin and rescue the sarcolemmal permeability defects accompanying dystrophin deficiency.65,66
Dystrophin is also enriched in costameres of cardiac muscle.67 Like skeletal muscle, dystrophin-
deficient cardiac myocytes are abnormally vulnerable to mechanical stress-induced contractile
failure and injury.68,69 Finally, knockout of the dystroglycan or sarcoglycan complexes also
causes muscular dystrophy that is accompanied by defects in sarcolemmal integrity.70-79 When
taken together, the above studies provide compelling evidence that the dystrophin-glycoprotein
complex mainly functions to anchor the sarcolemma to costameres and stabilize it against the
mechanical forces transduced through costameres during muscle contraction or stretch.
Expanding beyond the Dystrophin-Glycoprotein Complex
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Since its initial description in 1990, many additional proteins have been shown to interact with
different dystrophin-glycoprotein complex components (Fig. 4). Once the laminin α-chain G-
domain was identified as the binding site for α-dystroglycan,80 several other proteins containing
homologous G-domain modules were interrogated and shown to bind α-dystroglycan with high
affinity. The current list of such proteins includes agrins,81-84 neurexins85 and perlecan.86,87 Like
laminins, these proteins all bind to α-dystroglycan in a manner dependent on its oligosaccharide
modifications.88 In contrast, the chondroitin sulfate chains of the proteoglycan biglycan have
been shown to mediate its binding to the core protein of α-dystroglycan.89 While the functional
significance of α-dystroglycan binding to several different extracellular matrix molecules is not
fully clear, the results suggest that the dystroglycan complex may serve multiple roles that vary
with the extracellular ligand to which it is bound. That agrins, neurexins and perlecan have all
been implicated in various aspects of synapse formation or function.90 further suggests
participation by the dystroglycan complex in this process.
Figure 4
The Protein Interacting Network of the Dystrophin-Glycoprotein Complex. AQP4, aquaporin 4;
Cav-3, caveolin-3; nNOS, neuronal nitric oxide synthase; SAPK3, stress-activated protein kinase
3 For a full list of supporting references, refer to the supplementary (more...)
The Protein Interacting Network of the Dystrophin-Glycoprotein Complex. AQP4, aquaporin 4;
Cav-3, caveolin-3; nNOS, neuronal nitric oxide synthase; SAPK3, stress-activated protein kinase
3 For a full list of supporting references, refer to the supplementary information in 21 from
which this figure was redrawn.
Based on its sequence similarity with the calponin homology actin binding domains of β-spectrin
and α-actinin, the N-terminal domain of dystrophin was hypothesized to bind actin filaments.
Indeed, recombinant proteins encoding the dystrophin N-terminal domain do bind actin
filaments,91 but with relatively low affinity.92 In contrast, purified dystrophin-glycoprotein
complex bound actin filaments with substantially higher affinity compared to the isolated amino-
terminal domain. The stoichiometry of binding however, suggested a more extensive lateral
association between dystrophin and actin filaments than could be explained by actin binding
solely through the N-terminal domain alone.93 Mapping of the actin binding sites in dystrophin
through F-actin cosedimentation of fragments after limited proteolysis led to the identification of
a second actin binding site situated in the middle third of the dystrophin rod domain.93 The
spectrin-like repeats in this novel actin binding site were found to carry an excess of basic amino
acid residues and were shown to bind acidic actin filaments largely through electrostatic
interaction.94 Because the middle rod actin binding site of dystrophin was separated from the
amino-terminal actin binding domain by ˜1200 amino acids, the two sites were proposed to act in
concert to effect an extended lateral association that could account for the measured
stoichiometry of binding. In addition, the dystrophin-glycoprotein complex was shown to slow
depolymerization of actin filaments in vitro.93,95 These data supported a novel actin filament side-
binding model for dystrophin and are entirely consistent with a role for the dystrophin-
glycoprotein complex in mechanically coupling the sarcolemma with actin filaments of the
costameric cytoskeleton.64
The development of two-hybrid methodologies for the identification of protein-protein
interactions has led to the discovery of several proteins that interact with the dystrophin-
glycoprotein complex. Two-hybrid screens using α-dystrobrevin as bait identified several novel
proteins.96-98 Two of these proteins, synemin/desmuslin98 and syncoilin,99 are structurally related
to intermediate filament proteins and interact with the classical intermediate filament protein
desmin. Interestingly, mice knocked out for either α-dystrobrevin100 or desmin101,102 exhibit
skeletal and cardiomyopathy, which suggests that mechanical coupling of the dystrophin-
glycoprotein complex to the intermediate filament cytoskeleton is necessary for normal muscle
function (see Chapter 5). Two hybrid screens using the cytoplasmic domains of sarcoglycans
identified a skeletal muscle-specific form of filamin (γ-filamin) as a sarcoglycan interacting
protein.103 Like dystrophin, filamin contains an N-terminal calponin homology actin binding
domain and a large number of repeated motifs, although the repeats in filamin differ in structure
from those in dystrophin. Interestingly, filamin A is recruited to focal adhesions of nonmuscle
cells in response to local mechanical stress applied via collagen-coated magnetic beads.104 Since
γ-filamin is upregulated and recruited to the sarcolemma in dystrophin-deficient muscle,103 it is
tempt- ing to speculate that the dystrophin-deficient costamere may “sense” increased
mechanical stress and attempt to compensate by recruitment of filamin. In addition to γ-filamin,
several more actin binding proteins of costameres are upregulated in dystrophin-deficient muscle
including the cytolinker plectin,105 the integrin-associated proteins talin and vinculin106 and the
laminin receptor α7β1 integrin.107,108 While not normally present at costameres, the dystrophin
homologue utrophin is upregulated and recruited to costameres in dystrophin-deficient
muscle.64,65 Based on the protein interaction network illustrated in (Fig. 4), it seems most
reasonable that all of these structural proteins are upregulated by the dystrophin-deficient muscle
cell in an attempt to compensate for the absence of dystrophin by fortifying the weakened
costamere through the recruitment of parallel mechanical linkages. Because dystrophy persists,
these parallel linkages are either not completely redundant with the dystrophin-glycoprotein
complex, or the compensatory upregulation/recruitment is incomplete. In support of the latter
possibility, transgenic overexpression of utrophin37,53,54 or α7 integrin109 has been shown to further
compensate for dystrophin deficiency. Thus, many of the proteins found to interact with the
dystrophin-glycoprotein complex, or upregulated in its absence, appear to couple the complex
with other structural elements of muscle, or form parallel mechanical links between the
sarcolemma and myofibrillar apparatus. As such, these findings further reinforce an important
mechanical function for the dystrophin-glycoprotein complex.
An Engineering Design Analogy
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In many respects, the bulk of experimental data indicate that the dystrophin-glycoprotein
complex functions in a manner analogous to the two-by-four (˜2 inch × 4 inch) timbers used to
frame the typical American stick house. The architect utilizes two-by-fours as one structural
element of a sturdy support matrix (ie., the costamere) intended to securely hold in place
weatherproof siding and shingles (ie., the sarcolemma) as well as doors and windows (ie., ion
channels and pumps) that allow for controlled movement of occupants, air and light both into
and out of the house. When built to the architect's specifications, the house (or normal muscle
cell) can withstand the stress imposed on it by extremes in weather such as high winds or heavy
snowfall (or muscle contraction). If, however, the house is built during a shortage of two-by-
fours (ie., the dystrophin-deficient muscle cell), the carpenter may be forced to substitute two-by-
two timbers instead (ie., compensatory upregulation of partially redundant structural proteins).
Such an alteration from original design may indeed allow the carpenter to construct a house that
stands in calm weather. Conversely, the compromised structure may distort sufficiently under the
force of gravity to cause doors and windows to stick or not close tightly. Moreover, the house
built with substandard structural elements is certainly less likely to remain intact when more
severe weather strikes.
Up to this point, the dystrophin-glycoprotein complex as two-by-four analogy has not taken into
account that several interacting proteins suggest additional roles for the dystrophin-glycoprotein
complex in organizing molecules involved in cellular signaling (Fig. 4). For example, α-
syntrophin anchors neuronal nitric oxide synthase to the sarcolemma,110 which is necessary to
properly regulate vascular perfusion in active muscle.111,112 Other data indicate that MAP kinase
signaling pathways are perturbed in dystrophin-deficient muscle.113-115 Because the putative
role(s) for the dystrophin-glycoprotein complex in cell signaling will no doubt be elaborated in
subsequent chapters, the reader may be left wondering whether and how a role in signaling fits
with its well-supported mechanical function. However, I believe the dystrophin-glycoprotein
complex as two-by-four analogy fits well with its role in anchoring signaling molecules and also
can explain the signaling perturbations observed in dystrophin-deficient muscle. While the
architect clearly intended the two-by-fours as structural support for the weather-proofing and
controlled entry components of the house, this primary function does not prevent the electrician,
plumber, telephone and cable television installers from subsequently utilizing the two-by-four
framework as a support to route and organize additional regulatory and communication systems
(ie., cell signaling pathways) that further enhance functionality of the house. These additional
systems would very reasonably be expected to malfunction in a house constructed of substandard
structural components (ie., two-by-twos instead of two-by-fours) as a secondary consequence of
its distortion under gravity or when challenged by more stringent weather conditions.
Alternatively, one could as reasonably argue that mechanical distortion of the structurally weak
two-by-two framework house may cause a short in the electrical system (ie., altered cell
signaling) that in turn destroys the house by catastrophic fire (ie., apoptosis). In either case, I
believe the architect could successfully argue that compromised mechanical integrity precipitated
destruction of the house (and that was not his, but the carpenter's fault!). The mere association of
signaling molecules with the dystrophin-glycoprotein complex and perturbations of signal
transduction pathways in dystrophin-deficient muscle are not sufficient evidence to refute the
compelling data supporting a primary mechanical function for the complex. Moreover, such data
fail to provide compelling support that the dystrophin-glycoprotein complex actively regulates
cellular signaling, or that altered signaling initiates the pathologies observed in dystrophin-
deficient muscle. While these hypotheses certainly remain attractive (especially with respect to
development of treatments for muscular dystrophy), the current challenge to the field is to design
and perform experiments that rigorously test their validity.
In at least one respect, the dystrophin-glycoprotein complex as two-by-four analogy fails. When
a house becomes too small for its occupants, the two-by-fours supporting static walls are
demolished in order to expand rooms. In the case of muscle however, cells simultaneously grow
under the influence of muscle contraction so the “two-by-four” framework of muscle cells must
be sufficiently dynamic to expand with growth while simultaneously protecting against stress-
induced membrane damage. Several studies have demonstrated that the dystrophin-glycoprotein
complex and costameres are indeed dynamic structures capable of remodeling in vivo.21
However, a remaining challenge is to understand how such fascinating and opposing functions
are effected at the molecular level, or perhaps at the level of interacting protein networks.
Acknowledgements
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I thank Ariana Combs and Inna Rybakova for the blot images used in (Fig. 1) and Kevin
Sonnemann for helpful discussions. The author is supported by grants from the Muscular
Dystrophy Association and the National Institutes of Health (AR42423).
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Copyright © 2000-2011, Landes Bioscience and Springer Science+Business Media.
Contents

Table of Contents Page

• Adhesion Molecules
○ Paramyxovirus Entry
○ Biological Roles of Prion Domains
○ The Role of Neuropilin in Vascular and Tumor Biology
○ Structural and Functional Relation of Neuropilins
○ Neuropilin and Its Ligands in Normal Lung and Cancer
○ Neuropilin and Class 3 Semaphorins in Nervous System Regeneration
• Aging
○ Yeast RecQ Helicases: Clues to DNA Repair, Genome Stability and
Aging
○ Sensory Influence on Homeostasis and Lifespan: Molecules and Circuits
○ Post-Translational Modification of Cellular Proteins by Ubiquitin and
Ubiquitin-Like Molecules: Role in Cellular Senescence and Ageing
• Angiogenesis
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
 ○ Vascular Endothelial Growth Factor in Malignant Disease of the Central
Nervous System
○ Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-
Endothelial Cells: Autocrine Signalling by VEGF
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
• Apoptosis
○ Autophagy in Caenorhabditis elegans
○ Apoptosis Dependent and Independent Functions of Caspases
○ The Role of Caspases in Modulation of Cytokines and Other Molecules
in Apoptosis and Inflammation
○ Caspases, Bcl-2 Family Proteins and Other Components of the Death
Machinery: Their Role in the Regulation of the Immune Response
○ Learning from Deficiency: Gene Targeting of Caspases
○ Caspase Activation in Cancer Therapy
○ Caspase-Independent Cell Death Mechanisms
○ Caspases as Targets for Drug Development
○ In Situ Activation of Caspases Revealed by Affinity Labeling Their
Enzymatic Sites
• Atherosclerosis
○ Antigen Recognition by γδ T-Cells
• Autoimmunity
○ Targeting Antigen-Specific T Cells for Gene Therapy of Autoimmune
Disease
○ Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-
Induced Arthritis
○ Cytokines in the Treatment and Prevention of Autoimmune Responses
○ Involvement of Cytokines in the Pathogenesis of Systemic Lupus
Erythematosus
○ Gene Therapy-Based Approach for Immune Tolerance Induction Using
Recombinant Immunoglobulin Carriers
○ Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune
Thrombocytopenic Purpura
○ Gastroenterologic and Hepatic Diseases
○ Inflammatory Myopathies: Dermatomyositis, Polymyositis and Inclusion
Body Myositis
○ Immunogene Therapy with Nonviral Vectors
○ Cytokines and Chemokines in Autoimmune Disease: An Overview
○ CTLA-4 in Type 1 Diabetes Mellitus
 ○ 4-1BB as a Therapeutic Target for Human Disease
• Bioinformatics
○ Prediction of Protein Function Two Basic Concepts and One Practical
Recipe
• Biomaterials
○ Regulation of Medical Devices
○ Tissue Engineering Constructs and Commercialization
• Biosurfactants
○ Screening Concepts for the Isolation of Biosurfactant Producing
Microorganisms
• Biotechnology
○ Use of piggyBac and a Sindbis Virus for Foreign Gene Expression and
RNAi in the Silkworm
○ Molecular Properties of Voltage-Gated Calcium Channels
○ Why Government Is the Problem (and What to Do about It)
○ Transgenic Analysis of the Biological Functions of a Doublesex
Homologue in Bombyx mori
○ Carbon Nanostructures as a New High-Performance Platform for MR
Molecular Imaging
○ Foundations of E-Cell Simulation Environment Architecture
○ Electrophysiological Simulation of Developmental Changes in Action
Potentials of Cardiomyocytes
○ Distributed Cell Biology Simulations with the E-Cell System
○ Bacterial Vectors for RNAi Delivery
○ HSV as a Vector in Vaccine Development and Gene Therapy
• Cancer Development
○ Epithelial-Mesenchymal Transitions in Human Cancer
• Cancer Genetics
○ Cellular Functions of Menin
• Cancer Metastasis
○ Integrins in Cancer Cell Invasion
○ The Plasminogen Activation System in Cell Invasion
○ Maspin: Functional Insights from a Structural Perspective
○ Maspin and Pericellular Plasminogen Activation in Cell-Matrix
Interaction
○ Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating
Integrin Expression and Function
○ The Role of Maspin in Tumor Progression and Normal Development
 ○ The Role of Maspin in Human Placental Development
○ Keratinocyte Interactions with Fibronectin during Wound Healing
• Cell Biology
○ Intracellular Membrane Fusion
○ The Golgi Apparatus
○ Clathrin-Mediated Endocytosis
○ Decoding the Signaling Mechanism of Toll-Like Receptor 4 Pathways in
Wild Type and Knockouts
○ Carrier Motility
○ The Exocytic Pathway and Development
○ Memory Th1/Th2 Cell Generation Controlled by Schnurri-2
○ The “O” Class: Crafting Clinical Care with FoxO Transcription Factors
○ FOXP Genes, Neural Development, Speech and Language Disorders
○ Regulation and Coordination of Intracellular Trafficking: An Overview
○ Overview of Intracellular Compartments and Trafficking Pathways
○ Sumoylation as a Signal for Polyubiquitylation and Proteasomal
Degradation
○ Studies on the Very Large G Protein–Coupled Receptor From Initial
Discovery to Determining Its Role in Sensorineural Deafness in Higher
Animals
○ Autosomal Lyonization of Replication Domains During Early Mammalian
Development
○ X Chromosome Inactivation and Embryonic Stem Cells
○ NOTCH SIGNALING AND THE DEVELOPING HAIR FOLLICLE
○ NOTCH SIGNALING AND THE GENERATION OF CELL DIVERSITY IN
DROSOPHILA NEUROBLAST LINEAGES
○ THE NEURAL BASIS OF SEMANTIC AND EPISODIC FORMS OF SELF-
KNOWLEDGE: Insights from Functional Neuroimaging
• Cell Cycle
○ The Restriction Point of the Cell Cycle
○ DNA Damage-Independent Checkpoints from Yeast to Man
○ The Regulation of p53 Growth Suppression
○ Functional Interactions Between BRCA1 and the Cell Cycle
○ The Evolution of CDK-Activating Kinases
○ CDK-Activating Kinases in Higher Plants
○ Activating Phosphorylation of Cyclin-Dependent Kinases in Budding
Yeast
• Cell Invasion
○ Matrix Metalloproteinases in Cancer Cell Invasion
• Cell Metabolism
○ Theory of Organelle Biogenesis: A Historical Perspective
○ Microfibril-Associated Glycoprotein-1 (MAGP-1) and Other Non-fibrillin
Macromolecules Which May Possess a Functional Association with the
10 nm Microfibrils
○ Synaptic Endosomes
○ Endocytosis of Receptor Tyrosine Kinases: Implications for Signal
Transduction by Growth Factors
○ Macroautophagy in Mammalian Cells
○ Plant Lipocalins
○ The Plasma Lipocalins α1-Acid Glycoprotein, Apolipoprotein D,
Apolipoprotein M and Complement Protein C8γ
○ Molecular Biology of the OXPHOS System
○ Bacterial Lipocalins: Origin, Structure, and Function
○ Chaperone-Mediated Autophagy
○ Regulation of Paracellular Transport across Tight Junctions by the Actin
Cytoskeleton
○ Entry into the Endoplasmic Reticulum: Protein Translocation, Folding
and Quality Control
○ Tight Junction Proteins and Cancer
○ Membrane Resealing Mediated by Lysosomal Exocytosis
○ Transcriptional Regulation of Keratin Gene Expression
○ Lysosomal Proteases: Revival of the Sleeping Beauty
○ Preprotein Translocation through the Sec Translocon in Bacteria
○ Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a
RELevant Role in Cancer
○ Nuclear Import of Agrobacterium T-DNA
○ Keratins As Targets in and Modulators of Liver Diseases
○ Retinol Binding Protein and Its Interaction with Transthyretin
○ Keratin Intermediate Filaments and Diseases of the Skin
○ Important Mammalian Respiratory Allergens Are Lipocalins
○ Lipocalin Receptors: Into the Spotlight
○ α1-Microglobulin
○ Lipocalins in Clinical Medicine
○ Lysosomal Storage Disorders
○ Lipocalins in Arthropoda: Diversification and Functional Explorations
○ Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Glycodelin: A Lipocalin with Diverse Glycoform-Dependent Actions
○ Nonsecretory, Regulated Exocytosis: A Multifarious Mechanism
Employed by Cells to Carry Out a Variety of Functions
○ Protein Misassembly: Macromolecular Crowding and Molecular
Chaperones
○ Molecular Interaction Network of the Hsp90 Chaperone System
○ The Synapsins and the Control of Neuroexocytosis
○ Hsp90 and Developmental Networks
○ A Common Binding Site for Actin-Binding Proteins on the Actin Surface
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Cell-Free Synthesis of Defined Protein Conjugates by Site-directed
Cotranslational Labeling
○ Reverse Engineering Models of Cell Cycle Regulation
○ Nuclear Import of Plant Proteins
○ Dynamic Connections of Nuclear Envelope Proteins to Chromatin and
the Nuclear Matrix
○ Nuclear Envelope Dynamics in Drosophila Pronuclear Formation and in
Embryos
○ Nuclear Envelope Breakdown and Reassembly in C. elegans:
Evolutionary Aspects of Lamina Structure and Function
○ Laminopathies: One Gene, Two Proteins, Five Diseases..
○ Dynamics of Nuclear Envelope Proteins During the Cell Cycle in
Mammalian Cells
○ Calnexin and Calreticulin, Molecular Chaperones of the Endoplasmic
Reticulum
○ Calreticulin-Mediated Nuclear Protein Export
○ Calreticulin and the Endoplasmic Reticulum in Plant Cell Biology
○ Calnexin and Calreticulin, ER Associated Modulators of Calcium
Transport in the ER
○ ER Calcium and ER Chaperones: New Players in Apoptosis?
○ Calreticulin in Cytotoxic Lymphocyte-Mediated Cytotoxicity
○ A Role for Calreticulin in the Clearance of Apoptotic Cells and in the
Innate Immune System
 ○ Calreticulin and Tumor Suppression
○ Cell Surface Calreticulin: Role in Signaling Thrombospondin Anti-
Adhesive Activity
○ Calreticulin Regulation of Lung Endothelial NOS Activity
• Channels and Transporters
○ Cell-Cell Fusion: Transient Channels Leading to Plasma Membrane
Merger
○ Anion Conduction by CFTR: Mechanisms and Models
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Voltage-Dependent Inactivation of Voltage Gated Calcium Channels
○ A Brief History of Calcium Channel Discovery
○ Block of Voltage-Gated Calcium Channels by Peptide Toxins
○ Calcium Channel Block and Inactivation: Insights from Structure-
Activity Studies
○ Ca2+ Chemistry, Storage and Transport in Biologic Systems: An
Overview
○ Hepatic Copper Transport
○ Drug-Induced Cholestatic Liver Disease
○ Cell-Cell Channels and Their Implications for Cell Theory
○ Cytoplasmic Bridges in Volvox and Its Relatives
○ Gap Junctions: Cell-Cell Channels in Animals
○ The Tetrahymena Conjugation Junction
○ Mating Cell-Cell Channels in Conjugating Bacteria
○ Fusome as a Cell-Cell Communication Channel of Drosophila Ovarian
Cyst
○ Channels across Endothelial Cells
○ Cytonemes as Cell-Cell Channels in Human Blood Cells
○ Vegetative Hyphal Fusion in Filamentous Fungi
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Genetics, Mutations, and Polymorphisms
○ Hepatocyte Transplantation and Liver-Directed Gene Therapy
○ Phylogeny of Major Intrinsic Proteins
• Chaperones
○ Nucleotide Exchange Factors for Hsp70 Molecular Chaperones
○ Functions of the Hsp90-Binding FKBP Immunophilins
• Circadian Rhythms
○ Circadian Organization in the Algal Flagellate Euglena
• Coagulation
○ Regulation of Tissue Factor Expression
○ Factor XI, TAFI and DIC
○ Cytokines as Regulators of Coagulation
○ DIC at the Intersection of the Thrombotic, Fibrinolytic and Inflammatory
Axes
○ Genetic Risk Factors for Disseminated Intravascular Coagulation
○ Endothelial Cell Perturbation and Disseminated Intravascular
Coagulation
○ Blood-Borne Tissue Factor (Including Microparticles)
• Cytokines/Growth Factors
○ IL-10 Gene Polymorphisms in Transplantation
○ The Structure of the Type 1 Insulin-Like Growth Factor Receptor
○ Interleukin-10 Gene Polymorphisms and Cancer
○ The Role of IL-10 in Autoimmune Pathology
• Development
○ Embryonic Salivary Gland Branching Morphogenesis
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Integrins and Development: Integrins in Skeletal Cell Function and
Development
○ Membrane Lipid Rafts and Their Role in Axon Guidance
○ Epithelial-Mesenchymal Transformation in the Embryonic Heart
○ GSK3-Signal Regulation of Pattern Formation in Dictyostelium: Wnt-
Like Pathways During Non-Canonical Multicellular Development
○ Functional and Ecological Effects of Isoform Variation in Insect Flight
Muscle
○ Change of Epithelial Fate: Lessons from Gastrulation in Drosophila
○ Cadherin-Mediated Cell-Cell Adhesion and the Microtubule Network
○ TGFβ-dependent Epithelial-Mesenchymal Transition
○ Branching Morphogenesis of the Prostate
○ Expression and Function of Pitx2 in Chick Heart Looping
○ Neural Crest and the Development of the Enteric Nervous System
○ Matrix Metalloproteases and Epithelial-to-Mesenchymal Transition:
Implications for Carcinoma Metastasis
○ Whole Genome Approaches to Studying Drosophila Muscle
Development
○ Muscle Morphogenesis: The Process of Embryonic Myoblast Fusion
○ Development of the Larval Somatic Musculature
○ The Pathophysiological Role of Impaired Calcium Handling in Muscular
Dystrophy
○ X-Ray Diffraction of Indirect Flight Muscle from Drosophila in Vivo
○ The Sarcoglycans
○ The Role of Insulin-like Growth Factors in the Epithelial to Mesenchymal
Transition
○ Epithelium–Mesenchyme Transitions Are Crucial Morphogenetic Events
Occurring During Early Development
○ How Is the Branching of Animal Blood Vessels Implemented?
○ Integrins and Associated Proteins in Drosophila Development
○ Roles for Integrins and Associated Proteins in the Haematopoietic
System
○ Development of the Cardiac Musculature
○ Shh/Gli Signaling During Murine Lung Development
○ New Perspectives in Shh Signalling?
○ Role of shh and Gli Signalling in Oligodendroglial Development
○ Branching Morphogenesis in Vertebrate Neurons
○ Sonic Hedgehog Signaling in the Developing and Regenerating Fins of
Zebrafish
○ Role of Hedgehog and Gli Signalling in Telencephalic Development
○ Structure and Function of the Dystrophin-Glycoprotein Complex
○ Caveolin-3 and Limb-Girdle Muscular Dystrophy
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Cranial Neural Crest and Development of the Head Skeleton
○ Mesoderm Formation in the Drosophila Embryo
○ Neural Crest Delamination and Migration: Integrating Regulations of
Cell Interactions, Locomotion, Survival and Fate
○ Insect Flight Muscle Chemomechanics
○ The Role of Integrins in Cell Migration
○ Neural Crest Cell Plasticity: Size Matters
○ Neural Crest Stem Cells
○ Integrins: An Overview of Structural and Functional Aspects
 ○ An Evolutionary Perspective on Eukaryotic Membrane Trafficking
○ Slits and Their Receptors
○ Origins and Evolution of Cotranslational Transport to the ER
○ Origins and Evolution of the Actin Cytoskeleton
○ Comparison of Muscle Development in Drosophila and Vertebrates
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
○ The Genetic Regulation of Pigment Cell Development
○ Origin and Evolution of Self-Consumption: Autophagy
○ The Contribution of the Neural Crest to the Vertebrate Body
○ Dorsoventral Patterning of the Brain: A Comparative Approach
○ VEGF and Endothelial Guidance in Angiogenic Sprouting
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ CtBP and Hematopoietic Transcriptional Regulators
○ A New Member of the CtBP/BARS Family from Plants: Angustifolia
○ Simulation of Human Erythrocyte Metabolism
○ A Model Library of Bacterial Chemotaxis on E-Cell System
○ CtBP3/BARS and Membrane Fission
○ Hsp70-Mediated Protein Refolding in E-Cell
○ VEGF Receptor Signalling in Vertebrate Development
○ Vascular and Nonvascular Roles of VEGF in Bone Development
○ Morphogenesis of Epithelial Appendages: Variations on Top of a
Common Theme and Implications in Regeneration
○ Wnt/Wingless Signaling in Drosophila
○ The Role of Wnt Signaling in Vertebrate Head Induction and the
Organizer-Gradient Model Dualism
○ The Wnt Gene Family and the Evolutionary Conservation of Wnt
Expression
○ Secreted Antagonists/Modulators of Wnt Signaling
○ Patterning the Vertebrate Neural Plate by Wnt Signaling
○ Wnt/Wg and Heart Development
○ Wnt Signaling and Cell Migration
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
• DNA Surveillance and Repair
 ○ Roles of Poly(ADP-Ribose) Metabolism in the Regulation of Centrosome
Duplication and in the Maintenance of Neuronal Integrity
○ PARP and the Release of Apoptosis-Inducing Factor from Mitochondria
○ DNA Damage Signaling through Poly(ADP-Ribose)
○ Dynamic Interaction between PARP-1, PCNA and p21waf1/cip1
○ Parp and Epigenetic Regulation
○ Genome Degradation by DNAS1L3 Endonuclease: A Key PARP-1-
Regulated Event in Apoptosis
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Role of Poly-ADP-Ribosylation in Cancer Development
○ The Fanconi Anemia/BRCA Pathway: FANCD2 at the Crossroad between
Repair and Checkpoint Responses to DNA Damage
○ Fluorescence-Signaling Nucleic Acid-Based Sensors
○ Trichothiodystrophy: A Disorder Highlighting the Crosstalk between
DNA Repair and Transcription
○ Mobile Genetic Elements of Malaria Vectors and Other Mosquitoes
○ Orchestration of Telomeres and DNA Repair Factors in Mammalian
Cells: Implications for Cancer and Ageing
○ Mechanisms of DNA Damage and Repair in Alzheimer Disease
○ Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks
in Mammalian Cells
• DNA Vaccines
○ The Introduction of New DNA Vaccines into Developing Countries
• Drug Design
○ A Conceptual Framework
○ Modeling Structure-Activity Relationships
○ Prediction of Drug-Like Properties
○ Evolutionary De Novo Design
○ Analysis of Chemical Space
• Endocrinology
○ Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated
Vesicle Exocytosis
○ Subcellular Compartmentalization of Insulin Signaling Processes and
GLUT4 Trafficking Events
○ Insulin Action in the Islet β-Cell
○ What Is Osteoporosis?
○ Insulin and IGF-I Receptor Structure and Binding Mechanism
 ○ Insulin Resistance
○ Insulin Action Gene Regulation
• Evolution
○ Ribozyme-Catalyzed Genetics
○ Origin and Evolution of DNA and DNA Replication Machineries
○ Life in a Tenuous Universe
○ The Frame for New Hypotheses of Evolution
○ Genomism and the Nature Trail
○ The Origin of Complexity
○ Our Young Planet: One Is Not a Choice
○ The Condensation of Life
○ The Origins of Species
○ Development of Biological Potential
○ Thoughts on Multi-Cellularity: How Nature Got Around Darwin
○ Natura non facit saltum (Nature does nothing in jumps)
○ The Invariance Concept
○ On the Evolution of Humans
○ Molecular Geneology
○ Experiments in Evolution
○ Quintessence
○ The Scope of Selection
• Extracellular Matrix
○ The Biogenesis and Cell Biology of Peroxisomes in Human Health and
Disease
○ Assembly of Microfibrils
• Gastroenterology
○ Nerve Regulation of Cholangiocyte Functions
○ Functional Heterogeneity of the Intrahepatic Biliary Epithelium
○ Bile Acid Interactions with Cholangiocytes
○ Estrogen Regulation of Cholangiocyte Proliferation
○ Nerve Regulation of Cholangiocyte Functions
○ Vascularization of the Intrahepatic Biliary Tree and Its Role in the
Regulation of Cholangiocyte Growth
○ Cytokine Regulation of Cholangiocyte Growth
○ Hyperemesis Gravidarum and Maternal Liver Disease
○ The Liver in Normal Pregnancy
 ○ Spectrum of Maternal Liver Disease
• Gene Expression
○ Stochastic Gene Expression: Dominance, Thresholds and Boundaries
○ Biological Consequences of Dosage Dependent Gene Regulation in
Multicellular Eukaryotes
○ GAGA: Structural Basis for Single Cys2His2 Zinc Finger-DNA Interaction
○ Identification of Mammalian E2F Regulatory Networks Using DNA
Microarray Hybridization Analyses
○ Homing Endonuclease I-TevI: An Atypical Zinc Finger with a Novel
Function
○ A Novel Test Statistic for the Identification of Local Selective Sweeps
Based on Microsatellite Gene Diversity
○ Periodic Selection and Ecological Diversity in Bacteria
○ LIM Domain and Its Binding to Target Proteins
○ MDM2: RING Finger Protein and Regulator of p53
○ Inferring Evolutionary History through Inter- and Intraspecific DNA
Sequence Comparison: The Drosophila janus and ocnus Genes
○ Selective Sweep in the Evolution of a New Sperm-Specific Gene in
Drosophila
○ The Superfamily of SCAN Domain Containing Zinc Finger Transcription
Factors
○ Putative Roles of kin17, a Mammalian Protein Binding Curved DNA, in
Transcription
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ A Zinc Ribbon Motif Is Essential for the Formation of Functional
Tetrameric Protein Kinase CK2
○ Rapid Evolution of Sex-related Genes: Sexual Conflict or Sex-specific
Adaptations?
○ Repression of Transcription by Curved DNA and Nucleoid Protein H-NS:
A Mode of Bacterial Gene Regulation
○ Curved DNA and Transcription in Eukaryotes
○ PNA and Oligonucleotide Inhibitors of Human Telomerase
○ Possible Roles of DNA Supercoiling in Transcription
○ MDM2: RING Finger Protein and Regulator of p53
○ Gene Regulatory Networks
○ Do DNA Triple Helices or Quadruplexes Have a Role in Transcription?
○ The Biology of Telomeres in Hypotrichous Ciliates
○ Scaling Laws in the Functional Content of Genomes: Fundamental
Constants of Evolution?
○ Regulation of Cardiomyocyte Proliferation and Apoptosis
○ Cell Cycle Reactivation in Skeletal Muscle and Other Terminally
Differentiated Cells
○ The Role of Unusual DNA Structures in Chromatin Organization for
Transcription
○ Molecular Mechanisms of Male Sex Determination: The Enigma of SRY
○ DNA: Alternative Conformations and Biology
○ Curved DNA and Prokaryotic Promoters: A Mechanism for Activation of
Transcription
○ Scale-Free Evolution: From Proteins to Organisms
○ Bioinformatics: Mystery, Astrology or Service Technology?
○ Extracting Information for Meaningful Function Inference Through Text-
Mining
○ Microarrays and Gene Regulation Networks in Yeast
○ Transcriptional Repression by the CtBP Corepressor in Drosophila
○ Structural Determinants of CtBP Function
○ Analytical Evolutionary Model for Protein Fold Occurrence in Genomes,
Accounting for the Effects of Gene Duplication, Deletion, Acquisition
and Selective Pressure
○ Power Law Correlations in DNA Sequences
○ Transcriptional Networks in Mammalian Gene Regulation
○ DNA Primer Extension by Telomerase
○ Transcriptional Profiling of the Hepatic Growth Response
○ Expression of Hox Genes in the Nervous System of Vertebrates
○ Telomeres: Guardians of Genomic Integrity or Double Agents of
Evolution?
○ Alternative Lengthening of Telomeres in Mammalian Cells
○ Evolution of Telomere Binding Proteins
○ Drosophila Telomeres: A Variation on the Telomerase Theme
○ Telomerase Activity as a Marker of Tumor Cell Survival to Evaluate
Sensitivity of Neoplastic Cells to Cancer Treatment
○ Myotonic Dystrophy: Discussion of Molecular Basis
○ Roles for TERT and Telomerase in Cell Differentiation and Apoptosis
○ Molecular Mechanisms of TRS Instability
○ Yeast Telomerases: Structure, Mechanisms and Regulation
 ○ The Significance of Quantitative Evaluation of Telomerase Activity and
hTERT mRNA Expression in Colorectal Cancers
○ Human, Mouse and Yeast Telomerase
○ Telomerase in Mesothelioma: Diagnostic and Therapeutic Applications
○ Telomerase Activity in Neuroblastomas: A New Molecular Marker for
Treatment Stratification and Prognostic Grouping
○ Telomerase and Radiosensitivity of Human Tumors
• Heart
○ Origin of Mechanotransduction: Stretch-Activated Ion Channels
○ Regional Differences and Variability in Left Ventricular Wall Motion
• Heat Shock Proteins
○ Assembly of Protein Aggregates in Neurodegeneration: Mechanisms
Linking the Ubiquitin/Proteasome Pathway and Chaperones
○ The Role of Heat Shock Proteins during Neurodegeneration in
Alzheimer's, Parkinson's and Huntington's Disease
• Hematology
○ Other Proteins and Their Interactions with FA Gene Products
○ The Genetic Basis of Fanconi Anemia
○ The FANCC Gene and Its Products
• Immunology
○ Animal Models of OXPHOS Disorders
○ Molecular Recognition of Haptens by T Cells: More Than One Way to
Tickle the Receptor
○ Phospholipases and Phagocytosis
○ IgA and Mucosal Homeostasis
○ Carbohydrate-Based Targets and Vehicles for Cancer and Infectious
Diseases Vaccines
○ Small GTP Binding Proteins and the Control of Phagocytic Uptake
○ Calcium Signaling During Phagocytosis
○ Regulation of Phagocytosis by FcγRIIb and Phosphatases
○ Adding Complexity to Phagocytic Signaling: Phagocytosis-Associated
Cell Responses and Phagocytic Efficiency
○ V(D)J Recombination: Of Mice and Sharks
○ Opioid Receptors on Peripheral Sensory Neurons
○ Morphological Correlates of Immune-Mediated Peripheral Opioid
Analgesia
○ Functional Evidence of Pain Control by the Immune System
 ○ Opioid Receptor Expression and Intracellular Signaling by Cells
Involved in Host Defense and Immunity
○ Experimental Evidence for Immunomodulatory Effects of Opioids
○ The Immune-Suppressive Effects of Pain
○ Lipoxins as an Immune-Escape Mechanism
○ Dynamic Aspects of TCRα Gene Recombination: Qualitative and
Quantitative Assessments of the TCRα Chain Repertoire in Man and
Mouse
○ Viral TNF Inhibitors as Potential Therapeutics
○ CD8 T-Cell Memory Differentiation during Acute and Chronic Viral
Infections
○ Chromatin Mechanisms Regulating Gene Expression In Health And
Disease
○ Earthworm Immunity
○ TRIM PROTEINS AS RING FINGER E3 UBIQUITIN LIGASES
○ REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for
Treatment of Mast-Cell Related Diseases?
○ GASTROPOD IMMUNOBIOLOGY
○ MAST CELLS AND IMMUNOREGULATION/IMMUNOMODULATION
• Infectious Disease
○ Everything (or Almost Everything) You Want to Know about Genetically
Modified Mosquitoes for Malaria Control but Are (Maybe) Afraid to Ask
○ Predicting the Spread of a Transgene in African Malaria Vector
Populations: Current Knowledge and Limitations
○ Invasion and Intracellular Survival by Toxoplasma
○ Negative Signaling and Modulation of Macrophage Function in
Trypanosoma cruzi Infection
○ Pro-Inflammatory Responses in Macrophages during Toxoplasma
gondii Infection
○ Avoidance of Innate Immune Mechanisms by the Protozoan Parasite,
Leishmania spp
○ Insect Population Suppression Using Engineered Insects
○ Current and Emerging Approaches to Studying Invasion in
Apicomplexan Parasites
• Ischemia-Reperfusion
○ Therapeutic Utilities of SOD Mimetics: Cancer, Radiotherapy and SOD
Mimetics
○ Development of Manganic Porphyrin Mimetics of Superoxide Dismutase
Activity
 ○ Role of Superoxide in Post-Ischemic Liver Injury
○ Evaluation of a Superoxide Dismutase Mimetic As an Adjunct to
Interleukin 2 Based Cancer Therapy
• Medical
○ STATs and Infection
○ JAK/STAT Pathway Signalling in Drosophila Melanogaster
○ Disease Transmission Models for Public Health Decision-Making:
Designing Intervention Strategies for Schistosoma japonicum
○ Parameter Estimation and Site-Specific Calibration of Disease
Transmission Models
• Molecular Biology
○ RNA Modification Subsystems in the SEED Database
○ KIR Genes and Their Role in Spondyloarthropathies
○ Antibiotic Resistance in Bacteria Caused by Modified Nucleosides in
23S Ribosomal RNA
○ The “PACE” Concept Pointed at New Key Proteins Involved in RNA
Metabolism
○ DNA Demethylation
○ Adhesion-Dependent Modulation of Macrophage K+ Channels
○ Pseudouridine Formation, the Most Common Transglycosylation in RNA
○ Folate-Dependent Thymidylate-Forming Enzymes: Parallels between
DNA and RNA Metabolic Enzymes and Evolutionary Implications
○ The Interplay between RNA and DNA Modifications: Back to the RNA
World
○ Deciphering the Complex Enzymatic Pathway for Biosynthesis of
Wyosine Derivatives in Anticodon of tRNAPhe
○ Nucleic Acids Are Not Boring Long Polymers of Only Four Types of
Nucleotides: A Guided Tour
○ Chemokine Binding Proteins Encoded by Pathogens
○ Boomerangs, Bananas and Blimps: Structure and Function of F-BAR
Domains in the Context of the BAR Domain Superfamily
○ Gas7
○ Enzyme-RNA Substrate Recognition in RNA-Modifying Enzymes
• Nanomedicine
○ STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?
• Neurodegenerative Disease
○ DSD-1-Proteoglycan/Phosphacan and Receptor Protein Tyrosine
Phosphatase-Beta Isoforms During Development and Regeneration of
Neural Tissues
○ Interleukin-10 and Psoriasis
○ Idiopathic Parkinson's Disease: Staging an α-Synucleinopathy with a
Predictable Pathoanatomy
○ Chromosome 1 and Other Hotspots for Parkinson's Disease Genes
○ Fibroblast Growth Factors
○ Neuronal Survival and Cell Death Signaling Pathways
○ Paved with Good Intentions: The Link between Cell Cycle and Cell
Death in the Mammalian Central Nervous System
○ α-Synuclein Physiology and Membrane Binding
○ Na Channels and Ca2+ Channels of the Cell Membrane as Targets of
Neuroprotective Substances
○ Heat Shock Proteins and Neuroprotection
○ Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain
Ischemia Following Delayed Intravenous Administration of
Neurotrophins
○ Neuroprotective Strategies in Animal and in Vitro Models of Neuronal
Damage: Ischemia and Stroke
○ Vascular Endothelial Growth Factor
○ Cell Cycle and Chromosome Segregation Defects in Alzheimer's
Disease
○ Neuroprotective Activity of Metabotropic Glutamate Receptor Ligands
○ Excitatory Amino Acid Neurotoxicity
○ Dopamine and Parkinson's Disease
○ Neurotrophins
○ Overview Αβ Metabolism: From Alzheimer Research to Brain Aging
Control
○ β-Secretase: Progress and Open Questions
○ APP α-Secretase, a Novel Target for Alzheimer Drug Therapy
○ γ-Secretase and Presenilin
○ Functional Roles of APP Secretases
○ Proteolytic Degradation of Αβ by Neprilysin and Other Peptidases
○ Αβ Degradation by Endothelin-Converting Enzymes
○ Ab Metabolism in Cholesterol-Enriched Membrane Microdomains
○ Amyloid β-Protein in Low-Density Membrane Domains
○ Transport-Clearance Hypothesis for Alzheimer's Disease and Potential
Therapeutic Implications
○ Potential Role of Endogenous and Exogenous Ab Binding Molecules in
Ab Clearance and Metabolism
 ○ Modulating Amyloid β Levels by Immunotherapy: A Potential
Therapeutic Strategy for the Prevention and Treatment of Alzheimer's
Disease
• Neuropharmacology
○ Diurnal 5-HT Production and Melatonin Formation
○ Pineal Gland and Cancer—An Epigenetic Approach to the Control of
Malignancy: Evaluation of the Role of Melatonin
○ Cell Adhesion Molecules
○ Risks of Chronic Hypnotic Use
○ Sleep Hippocampal Theta Rhythm and Sensory Processing
○ Cannabinoid Receptors and Signal Transduction
○ Protein Kinase A
○ A Comparison of Visual Analog Scale and Categorical Ratings in
Assessing the Patient's Estimate of Sleep Quality
• Neuroscience
○ Role of Semaphorins during Axon Growth and Guidance
• Nucleus
○ Riboflavin and Methylenetetrahydrofolate Reductase
○ Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR)
and Overview of Mutations/Polymorphisms
○ Methylenetetrahydrofolate Reductase Polymorphisms:
Pharmacogenetic Effects
○ Assays for Methylenetetrahydrofolate Reductase Polymorphisms
• Oncogenes
○ p53's Dilemma in Transcription: Analysis by Microarrays
○ TP63, TP73: The Guardian's Elder Brothers
○ Modes of p53 Interactions with DNA in the Chromatin Context
• Oncology
○ Fever, Pyrogens and Cancer
○ Gene Expression Profiling in Malignant Lymphomas
○ Cytoreduction, Peritonectomy and Hyperthermic Antiblastic Peritoneal
Perfusion for the Treatment of Peritoneal Carcinomatosis
○ Hyperthermic Isolated Limb Perfusion
○ Intracavitary Hyperthermic Perfusion
○ Locoregional Hyperthermia
○ Transcription of rDNA in the Yeast Saccharomyces cerevisiae
○ Pre-Ribosomal RNA Processing in Multicellular Organisms
 ○ PDGF Pathways and Growth of Basal Cell and Squamous Cell
Carcinomas
○ Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A
Radiation
○ Influence of Tumor Microenvironment on Thermoresponse: Biologic and
Clinical Implications
○ Physical Background and Technical Realizations of Hyperthermia
○ Effects of Local and Whole Body Hyperthermia on Immunity
○ Thermo-Chemo-Radiotherapy Association: Biological Rationale,
Preliminary Observations on Its Use on Malignant Brain Tumors
○ Molecular Mechanisms of ErbB2-Mediated Breast Cancer
Chemoresistance
○ Future Perspectives of Interstitial and Perfusional Hyperthermia
○ Roles of Multidrug Resistance Genes in Breast Cancer Chemoresistance
○ Insulin-Like Growth Factors and Breast Cancer Therapy
○ Novel Approaches for Chemosensitization of Breast Cancer Cells: The
E1A Story
○ Whole Body Hyperthermia at 43.5-44°C: Dreams or Reality?
○ Overview of Resistance to Systemic Therapy in Patients with Breast
Cancer
○ Microarrays for Cancer Diagnosis and Classification
○ Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines:
Clinical Results
○ Cellular Interactions in Nasopharyngeal Carcinomas
• Protein
○ Structure, Function and Assembly of Flagellar Axial Proteins
○ Implications of 3D Domain Swapping for Protein Folding, Misfolding and
Function
○ From Artificial Antibodies to Nanosprings:The Biophysical Properties of
Repeat Proteins
○ The Budding Yeast PCH/F-BAR Proteins
○ Gas7
○ The Coronin Family of Proteins
○ Diversity of WD-repeat Proteins
○ A Brief History of the Coronin Family
○ Phylogenetic, Structural and Functional Relationships between WD-and
Kelch-Repeat Proteins
○ The Role of Mammalian Coronins in Development and Disease
 ○ Invertebrate Coronins
○ Evolutionary and Functional Diversity of Coronin Proteins
○ Coronin: The Double-Edged Sword of Actin Dynamics
○ Coronin 1 in Innate Immunity
○ Molecular Phylogeny and Evolution of the Coronin Gene Family
○ Coronin Structure and Implications
○ Nuclear APC
○ Role of Mammalian Coronin 7 in the Biosynthetic Pathway
○ Post-Targeting Functions of Signal Peptides
• Reproductive Biology
○ Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor
Functions during Epidermal Development and Disease
○ Bi-Directional Cell Trafficking During Pregnancy: Long-term
Consequences for Human Health
○ Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular
Immunity
○ The Role of Corticotropin-Releasing Hormone (CRH) on Implantation
and Immunotolerance of the Fetus
○ Characterization of Human Dendritic Cells at the Maternal-Fetal
Interphase
○ Important Role of Shh Controlling Gli3 Functions During the Dorsal-
Ventral Patterning of the Telencephalon
○ Spatial and Temporal Regulation of Hair Follicle Progenitors by
Hedgehog Signalling
○ MHC Molecules of the Preimplantation Embryo and Trophoblast
○ The Role of Regulatory T Cells in Materno-Fetal Tolerance
○ Cytogenetics of Human Sperm
○ Preimplantation Genetic Diagnosis (PGD): Screening for Aneuploidy in
Human Oocytes and Polar Bodies
○ Proteases and Their Cognate Inhibitors of the Serine and
Metalloprotease Subclasses, in Testicular Physiology
○ Antioxidant Systems and Oxidative Stress in the Testes
• RNA
○ Protein-Switched Ribozymes
○ Proteins Carrying One or More Unnatural Amino Acids
○ Therapies of Nonsense-Associated Diseases
○ All Termination Events Are Not Equal: Premature Termination in Yeast
Is Aberrant and Triggers NMD
○ Role of SMG-1-mediated Phosphorylation of Upf1 in NMD
○ NMD in Drosophila: A Snapshot into the Evolution of a Conserved
mRNA Surveillance Pathway
○ The snoRNPs and Related Machines: Ancient Devices That Mediate
Maturation of rRNA and Other RNAs
○ Trytophanyl-tRNA Synthetases
○ Tyrosyl-tRNA Synthetases
○ Cytokines, Chemokines and Their Receptors
○ Valyl-tRNA Synthetases
○ Protein-Induced RNA Switches in Nature
○ Class I Lysyl-tRNA Synthetases
○ Glutaminyl-tRNA Synthetases
○ Asparaginyl-tRNA Synthetases
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Aminoacyl-tRNA Synthetases and Disease
○ Human Upf Proteins in NMD
○ Phenylalanyl-tRNA Synthetases
○ Regulation of Gene Expression by Coupling of Alternative Splicing and
NMD
○ NMD and Human Disease
○ Polyadenylation and Degradation of RNA in Prokaryotes
○ Regulation of the Expression of Aminoacyl-tRNA Synthetases and
Translation Factors
○ Conformational Dynamics within the Ribosome
○ Tests of a Stereochemical Genetic Code
○ Evasion of Phagosome Lysosome Fusion and Establishment of a
Replicative Organelle by the Intracellular Pathogen Legionella
pneumophila
○ The End in Sight: Poly(A), Translation and mRNA Stability in Eukaryotes
○ Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized
for Gene Expression
○ Mechanism of Translation Initiation in Eukaryotes
○ A Prelude to Translational (Re)Initiation
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
 ○ Mitochondrial Aminoacyl-tRNA Synthetases
○ Transfer RNA Structure and Identity
○ Post-Transcriptional Gene Silencing in Plants
○ Turnover of Mature miRNAs and siRNAs in Plants and Algae
○ miRNAs need a Trim Regulation of miRNA Activity by Trim-NHL Proteins
○ Structural Components and Architectures of RNA Exosomes
○ C. ELEGANS STAR PROTEINS, GLD-1 AND ASD-2, REGULATE SPECIFIC
RNA TARGETS TO CONTROL DEVELOPMENT
• Signal Transduction
○ Genetic Susceptibility to Infectious Diseases Linked to NRAMP1 Gene in
Farm Animals
○ FasL-Independent Activation of Fas
○ Plant Metal Transporters with Homology to Proteins of the NRAMP
Family
○ Regulation of Bacterial MntH Genes
○ Physiological Roles and Mechanisms of Signaling by TRAF2 and TRAF5
○ Metal-ion Transporters— From Yeast to Human Diseases
○ The Function of Toll-Like Receptors
○ Regulation of the RhoGTPases by RhoGDI
○ How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-
GLI Signaling as Anti-Cancer Therapy?
○ Rho Family GTPases and Cellular Transformation
○ GLI Genes and Their Targets in Epidermal Development and Disease
○ Regulation of Cell Motility by Abl Family Kinases
○ The Patched Receptor: Switching On/Off the Hedgehog Signaling
Pathway
○ Shh Expression in Pulmonary Injury and Disease
○ Regulation of Cell Adhesion Responses by Abl Family Kinases
○ Abl Family Kinases in Mammalian Development
○ Abl and Cell Death
○ Mechanisms of Activation of Abl Family Kinases
○ Regulation of Cytoskeletal Dynamics and Cell Morphogenesis by Abl
Family Kinases
○ TRAFs in RANK Signaling
○ Abelson Family Protein Tyrosine Kinases and the Formation of Neuronal
Connectivity
○ The LTβR Signaling Pathway
 ○ Neurons, Neurotrophins and Ceramide Signaling: Do Domains and
Pores Contribute to the Dichotomy?
○ The Role of Serine/Threonine Protein Phosphatases in Ceramide
Signaling
○ Chaperone Effects on Prion and Nonprion Aggregates
○ Insights into the Modulation of Ceramide Metabolism by Naturally
Occurring and Synthetic Sphingolipid Analogs as Monitored by
Electrospray Tandem Mass Spectrometry
○ Ceramide Glycosylation and Chemotherapy Resistance
○ S-Modulin
○ Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by
Divalent Cations and Polyamines
○ Target Recognition of Guanylate Cyclase by Guanylate Cyclase-
Activating Proteins
○ Centrins, a Novel Group of Ca2+-Binding Proteins in Vertebrate
Photoreceptor Cells
○ The TRP Calcium Channel and Retinal Degeneration
○ Ca2+-dependent Control of Rhodopsin Phosphorylation: Recoverin and
Rhodopsin Kinase
○ The Complex of cGMP-gated Channel and Na/Ca2+, K Exchanger in Rod
Photoreceptors
○ RGS9-1 Phosphorylation and Ca2+
○ Ceramide in the Regulation of Neuronal Development: Two Faces of a
Lipid
○ Therapeutic Implications of Ceramide-Regulated Signaling Cascades
○ Photoreceptor Degeneration and Ca2+ Influx through Light-Activated
Channels of Drosophila
○ Regulation of the Rod Photoreceptor Cyclic Nucleotide-Gated Channel
○ Mouse Models to Study GCAP Functions in Intact Photoreceptors
○ Using Mutant Mice to Study the Role of Voltage-Gated Calcium
Channels in the Retina
○ Calcium Channels at the Photoreceptor Synapse
○ Biosynthesis of Sphingolipids in Plants (and Some of Their Functions)
○ Ceramide 1-Phosphate in Cell Survival and Inflammatory Signaling
• Stem Cells
○ Knockout Mouse Models of Cytokine Action in Hematopoietic Stem Cell
Regulation
○ Cytokines, Receptors and Signalling Pathways Involved in Macrophage
and Dendritic Cell Development
• Tissue Engineering
○ Scleroderma Lung Fibroblasts: Contractility and Connective Tissue
Growth Factor
○ Repair of Osteochondral Lesions
○ Regulatory Issues: Down to the Bare Bones
○ Anatomy and Physiology of the Spinal Cord
○ Encouraging Regeneration of Host Neurones: The Use of Peripheral
Nerve Bridges, Glial Cells or Biomaterials
○ Replacement of Specific Neuronal Populations in the Spinal Cord
○ Replacement of Specific Populations of Cells: Glial Cell Transplantation
into the Spinal Cord
○ In Vitro Endothelialization: Its Contribution Towards an Ideal Vascular
Replacement
○ Biocompatibility of Polyurethanes
○ Tissue Repair in Asthma: The Origin of Airway Subepithelial Fibroblasts
and Myofibroblasts
○ Functional Assessment of Fibroblast Heterogeneity by the Cell-Surface
Glycoprotein Thy-1
○ Pro-Invasive Molecular Cross-Signaling between Cancer Cells and
Myofibroblasts
○ Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinase and
Matrix Turnover and the Fate of Hepatic Stellate Cells
• Transplant
○ Polyomavirus Allograft Nephropathy: Clinico-Pathological Correlations
○ Metabolic Management
• Vaccines
○ Immune Responses to DNA Vaccines: Induction of CD8 T Cells
○ Neisseria meningitidis Vaccines
○ DNA Vaccines against Bacterial Pathogens
○ Dendritic Cells: Important Adjuvants During DNA Vaccination
• Viruses
○ A Role for Chemokine Activity in Alphavirus Pathogenesis: Evidence
from the Analysis of Polyarthritis and Myalgia Post-Ross River Virus
Infection
○ Evolutionary Aspects of Human Endogenous Retroviral Sequences
(HERVs) and Disease
○ Structure and Replication of Hepatitis Delta Virus RNA
○ Hepatitis Delta Virus RNA Editing
 ○ Hepatitis Delta Antigen and RNA Polymerase II
○ Transforming Activities of JC Virus Early Proteins
○ DNA Packaging by Bacteriophage P22
○ Regulation of T Cell Immunity by OX40 and OX40L
○ BK Virus, JC Virus and Simian Virus 40 Infection in Humans, and
Association with Human Tumors
○ The ø29 DNA Packaging Motor: Seeking the Mechanism
○ Phylogenomics and Molecular Evolution of Polyomaviruses
○ Urine Cytology Findings of Polyomavirus Infections
○ Immunity and Autoimmunity Induced by Polyomaviruses: Clinical,
Experimental and Theoretical Aspects
○ Soluble Chemokine Binding Proteins Encoded by Viruses
○ Bacteriophage Lambda Terminase and the Mechanism of Viral DNA
Packaging
○ DNA Packaging in Bacteriophage T4
○ Bacteriophage SPP1 DNA Packaging
○ Polyomavirus-associated Nephropathy in Renal Transplantation: Critical
Issues of Screening and Management
○ Entry of Herpesviruses into Cells: The Enigma Variations
< PrevNext >

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• Top▲
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
Madame Curie Bioscience Database [Internet].

Austin (TX): Landes Bioscience; 2000-.

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• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References

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Contents

Table of Contents Page

• Adhesion Molecules
○ Paramyxovirus Entry
○ Biological Roles of Prion Domains
○ The Role of Neuropilin in Vascular and Tumor Biology
○ Structural and Functional Relation of Neuropilins
○ Neuropilin and Its Ligands in Normal Lung and Cancer
○ Neuropilin and Class 3 Semaphorins in Nervous System Regeneration
• Aging
○ Yeast RecQ Helicases: Clues to DNA Repair, Genome Stability and
Aging
○ Sensory Influence on Homeostasis and Lifespan: Molecules and Circuits
○ Post-Translational Modification of Cellular Proteins by Ubiquitin and
Ubiquitin-Like Molecules: Role in Cellular Senescence and Ageing
• Angiogenesis
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
○ Vascular Endothelial Growth Factor in Malignant Disease of the Central
Nervous System
○ Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-
Endothelial Cells: Autocrine Signalling by VEGF
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
• Apoptosis
○ Autophagy in Caenorhabditis elegans
○ Apoptosis Dependent and Independent Functions of Caspases
 ○ The Role of Caspases in Modulation of Cytokines and Other Molecules
in Apoptosis and Inflammation
○ Caspases, Bcl-2 Family Proteins and Other Components of the Death
Machinery: Their Role in the Regulation of the Immune Response
○ Learning from Deficiency: Gene Targeting of Caspases
○ Caspase Activation in Cancer Therapy
○ Caspase-Independent Cell Death Mechanisms
○ Caspases as Targets for Drug Development
○ In Situ Activation of Caspases Revealed by Affinity Labeling Their
Enzymatic Sites
• Atherosclerosis
○ Antigen Recognition by γδ T-Cells
• Autoimmunity
○ Targeting Antigen-Specific T Cells for Gene Therapy of Autoimmune
Disease
○ Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-
Induced Arthritis
○ Cytokines in the Treatment and Prevention of Autoimmune Responses
○ Involvement of Cytokines in the Pathogenesis of Systemic Lupus
Erythematosus
○ Gene Therapy-Based Approach for Immune Tolerance Induction Using
Recombinant Immunoglobulin Carriers
○ Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune
Thrombocytopenic Purpura
○ Gastroenterologic and Hepatic Diseases
○ Inflammatory Myopathies: Dermatomyositis, Polymyositis and Inclusion
Body Myositis
○ Immunogene Therapy with Nonviral Vectors
○ Cytokines and Chemokines in Autoimmune Disease: An Overview
○ CTLA-4 in Type 1 Diabetes Mellitus
○ 4-1BB as a Therapeutic Target for Human Disease
• Bioinformatics
○ Prediction of Protein Function Two Basic Concepts and One Practical
Recipe
• Biomaterials
○ Regulation of Medical Devices
○ Tissue Engineering Constructs and Commercialization
• Biosurfactants
 ○ Screening Concepts for the Isolation of Biosurfactant Producing
Microorganisms
• Biotechnology
○ Use of piggyBac and a Sindbis Virus for Foreign Gene Expression and
RNAi in the Silkworm
○ Molecular Properties of Voltage-Gated Calcium Channels
○ Why Government Is the Problem (and What to Do about It)
○ Transgenic Analysis of the Biological Functions of a Doublesex
Homologue in Bombyx mori
○ Carbon Nanostructures as a New High-Performance Platform for MR
Molecular Imaging
○ Foundations of E-Cell Simulation Environment Architecture
○ Electrophysiological Simulation of Developmental Changes in Action
Potentials of Cardiomyocytes
○ Distributed Cell Biology Simulations with the E-Cell System
○ Bacterial Vectors for RNAi Delivery
○ HSV as a Vector in Vaccine Development and Gene Therapy
• Cancer Development
○ Epithelial-Mesenchymal Transitions in Human Cancer
• Cancer Genetics
○ Cellular Functions of Menin
• Cancer Metastasis
○ Integrins in Cancer Cell Invasion
○ The Plasminogen Activation System in Cell Invasion
○ Maspin: Functional Insights from a Structural Perspective
○ Maspin and Pericellular Plasminogen Activation in Cell-Matrix
Interaction
○ Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating
Integrin Expression and Function
○ The Role of Maspin in Tumor Progression and Normal Development
○ The Role of Maspin in Human Placental Development
○ Keratinocyte Interactions with Fibronectin during Wound Healing
• Cell Biology
○ Intracellular Membrane Fusion
○ The Golgi Apparatus
○ Clathrin-Mediated Endocytosis
 ○ Decoding the Signaling Mechanism of Toll-Like Receptor 4 Pathways in
Wild Type and Knockouts
○ Carrier Motility
○ The Exocytic Pathway and Development
○ Memory Th1/Th2 Cell Generation Controlled by Schnurri-2
○ The “O” Class: Crafting Clinical Care with FoxO Transcription Factors
○ FOXP Genes, Neural Development, Speech and Language Disorders
○ Regulation and Coordination of Intracellular Trafficking: An Overview
○ Overview of Intracellular Compartments and Trafficking Pathways
○ Sumoylation as a Signal for Polyubiquitylation and Proteasomal
Degradation
○ Studies on the Very Large G Protein–Coupled Receptor From Initial
Discovery to Determining Its Role in Sensorineural Deafness in Higher
Animals
○ Autosomal Lyonization of Replication Domains During Early Mammalian
Development
○ X Chromosome Inactivation and Embryonic Stem Cells
○ NOTCH SIGNALING AND THE DEVELOPING HAIR FOLLICLE
○ NOTCH SIGNALING AND THE GENERATION OF CELL DIVERSITY IN
DROSOPHILA NEUROBLAST LINEAGES
○ THE NEURAL BASIS OF SEMANTIC AND EPISODIC FORMS OF SELF-
KNOWLEDGE: Insights from Functional Neuroimaging
• Cell Cycle
○ The Restriction Point of the Cell Cycle
○ DNA Damage-Independent Checkpoints from Yeast to Man
○ The Regulation of p53 Growth Suppression
○ Functional Interactions Between BRCA1 and the Cell Cycle
○ The Evolution of CDK-Activating Kinases
○ CDK-Activating Kinases in Higher Plants
○ Activating Phosphorylation of Cyclin-Dependent Kinases in Budding
Yeast
• Cell Invasion
○ Matrix Metalloproteinases in Cancer Cell Invasion
• Cell Metabolism
○ Theory of Organelle Biogenesis: A Historical Perspective
○ Microfibril-Associated Glycoprotein-1 (MAGP-1) and Other Non-fibrillin
Macromolecules Which May Possess a Functional Association with the
10 nm Microfibrils
○ Synaptic Endosomes
○ Endocytosis of Receptor Tyrosine Kinases: Implications for Signal
Transduction by Growth Factors
○ Macroautophagy in Mammalian Cells
○ Plant Lipocalins
○ The Plasma Lipocalins α1-Acid Glycoprotein, Apolipoprotein D,
Apolipoprotein M and Complement Protein C8γ
○ Molecular Biology of the OXPHOS System
○ Bacterial Lipocalins: Origin, Structure, and Function
○ Chaperone-Mediated Autophagy
○ Regulation of Paracellular Transport across Tight Junctions by the Actin
Cytoskeleton
○ Entry into the Endoplasmic Reticulum: Protein Translocation, Folding
and Quality Control
○ Tight Junction Proteins and Cancer
○ Membrane Resealing Mediated by Lysosomal Exocytosis
○ Transcriptional Regulation of Keratin Gene Expression
○ Lysosomal Proteases: Revival of the Sleeping Beauty
○ Preprotein Translocation through the Sec Translocon in Bacteria
○ Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a
RELevant Role in Cancer
○ Nuclear Import of Agrobacterium T-DNA
○ Keratins As Targets in and Modulators of Liver Diseases
○ Retinol Binding Protein and Its Interaction with Transthyretin
○ Keratin Intermediate Filaments and Diseases of the Skin
○ Important Mammalian Respiratory Allergens Are Lipocalins
○ Lipocalin Receptors: Into the Spotlight
○ α1-Microglobulin
○ Lipocalins in Clinical Medicine
○ Lysosomal Storage Disorders
○ Lipocalins in Arthropoda: Diversification and Functional Explorations
○ Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Glycodelin: A Lipocalin with Diverse Glycoform-Dependent Actions
○ Nonsecretory, Regulated Exocytosis: A Multifarious Mechanism
Employed by Cells to Carry Out a Variety of Functions
 ○ Protein Misassembly: Macromolecular Crowding and Molecular
Chaperones
○ Molecular Interaction Network of the Hsp90 Chaperone System
○ The Synapsins and the Control of Neuroexocytosis
○ Hsp90 and Developmental Networks
○ A Common Binding Site for Actin-Binding Proteins on the Actin Surface
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Cell-Free Synthesis of Defined Protein Conjugates by Site-directed
Cotranslational Labeling
○ Reverse Engineering Models of Cell Cycle Regulation
○ Nuclear Import of Plant Proteins
○ Dynamic Connections of Nuclear Envelope Proteins to Chromatin and
the Nuclear Matrix
○ Nuclear Envelope Dynamics in Drosophila Pronuclear Formation and in
Embryos
○ Nuclear Envelope Breakdown and Reassembly in C. elegans:
Evolutionary Aspects of Lamina Structure and Function
○ Laminopathies: One Gene, Two Proteins, Five Diseases..
○ Dynamics of Nuclear Envelope Proteins During the Cell Cycle in
Mammalian Cells
○ Calnexin and Calreticulin, Molecular Chaperones of the Endoplasmic
Reticulum
○ Calreticulin-Mediated Nuclear Protein Export
○ Calreticulin and the Endoplasmic Reticulum in Plant Cell Biology
○ Calnexin and Calreticulin, ER Associated Modulators of Calcium
Transport in the ER
○ ER Calcium and ER Chaperones: New Players in Apoptosis?
○ Calreticulin in Cytotoxic Lymphocyte-Mediated Cytotoxicity
○ A Role for Calreticulin in the Clearance of Apoptotic Cells and in the
Innate Immune System
○ Calreticulin and Tumor Suppression
○ Cell Surface Calreticulin: Role in Signaling Thrombospondin Anti-
Adhesive Activity
○ Calreticulin Regulation of Lung Endothelial NOS Activity
• Channels and Transporters
○ Cell-Cell Fusion: Transient Channels Leading to Plasma Membrane
Merger
○ Anion Conduction by CFTR: Mechanisms and Models
 ○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Voltage-Dependent Inactivation of Voltage Gated Calcium Channels
○ A Brief History of Calcium Channel Discovery
○ Block of Voltage-Gated Calcium Channels by Peptide Toxins
○ Calcium Channel Block and Inactivation: Insights from Structure-
Activity Studies
○ Ca2+ Chemistry, Storage and Transport in Biologic Systems: An
Overview
○ Hepatic Copper Transport
○ Drug-Induced Cholestatic Liver Disease
○ Cell-Cell Channels and Their Implications for Cell Theory
○ Cytoplasmic Bridges in Volvox and Its Relatives
○ Gap Junctions: Cell-Cell Channels in Animals
○ The Tetrahymena Conjugation Junction
○ Mating Cell-Cell Channels in Conjugating Bacteria
○ Fusome as a Cell-Cell Communication Channel of Drosophila Ovarian
Cyst
○ Channels across Endothelial Cells
○ Cytonemes as Cell-Cell Channels in Human Blood Cells
○ Vegetative Hyphal Fusion in Filamentous Fungi
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Genetics, Mutations, and Polymorphisms
○ Hepatocyte Transplantation and Liver-Directed Gene Therapy
○ Phylogeny of Major Intrinsic Proteins
• Chaperones
○ Nucleotide Exchange Factors for Hsp70 Molecular Chaperones
○ Functions of the Hsp90-Binding FKBP Immunophilins
• Circadian Rhythms
○ Circadian Organization in the Algal Flagellate Euglena
• Coagulation
○ Regulation of Tissue Factor Expression
○ Factor XI, TAFI and DIC
○ Cytokines as Regulators of Coagulation
○ DIC at the Intersection of the Thrombotic, Fibrinolytic and Inflammatory
Axes
 ○ Genetic Risk Factors for Disseminated Intravascular Coagulation
○ Endothelial Cell Perturbation and Disseminated Intravascular
Coagulation
○ Blood-Borne Tissue Factor (Including Microparticles)
• Cytokines/Growth Factors
○ IL-10 Gene Polymorphisms in Transplantation
○ The Structure of the Type 1 Insulin-Like Growth Factor Receptor
○ Interleukin-10 Gene Polymorphisms and Cancer
○ The Role of IL-10 in Autoimmune Pathology
• Development
○ Embryonic Salivary Gland Branching Morphogenesis
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Integrins and Development: Integrins in Skeletal Cell Function and
Development
○ Membrane Lipid Rafts and Their Role in Axon Guidance
○ Epithelial-Mesenchymal Transformation in the Embryonic Heart
○ GSK3-Signal Regulation of Pattern Formation in Dictyostelium: Wnt-
Like Pathways During Non-Canonical Multicellular Development
○ Functional and Ecological Effects of Isoform Variation in Insect Flight
Muscle
○ Change of Epithelial Fate: Lessons from Gastrulation in Drosophila
○ Cadherin-Mediated Cell-Cell Adhesion and the Microtubule Network
○ TGFβ-dependent Epithelial-Mesenchymal Transition
○ Branching Morphogenesis of the Prostate
○ Expression and Function of Pitx2 in Chick Heart Looping
○ Neural Crest and the Development of the Enteric Nervous System
○ Matrix Metalloproteases and Epithelial-to-Mesenchymal Transition:
Implications for Carcinoma Metastasis
○ Whole Genome Approaches to Studying Drosophila Muscle
Development
○ Muscle Morphogenesis: The Process of Embryonic Myoblast Fusion
○ Development of the Larval Somatic Musculature
○ The Pathophysiological Role of Impaired Calcium Handling in Muscular
Dystrophy
○ X-Ray Diffraction of Indirect Flight Muscle from Drosophila in Vivo
○ The Sarcoglycans
○ The Role of Insulin-like Growth Factors in the Epithelial to Mesenchymal
Transition
○ Epithelium–Mesenchyme Transitions Are Crucial Morphogenetic Events
Occurring During Early Development
○ How Is the Branching of Animal Blood Vessels Implemented?
○ Integrins and Associated Proteins in Drosophila Development
○ Roles for Integrins and Associated Proteins in the Haematopoietic
System
○ Development of the Cardiac Musculature
○ Shh/Gli Signaling During Murine Lung Development
○ New Perspectives in Shh Signalling?
○ Role of shh and Gli Signalling in Oligodendroglial Development
○ Branching Morphogenesis in Vertebrate Neurons
○ Sonic Hedgehog Signaling in the Developing and Regenerating Fins of
Zebrafish
○ Role of Hedgehog and Gli Signalling in Telencephalic Development
○ Structure and Function of the Dystrophin-Glycoprotein Complex
○ Caveolin-3 and Limb-Girdle Muscular Dystrophy
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Cranial Neural Crest and Development of the Head Skeleton
○ Mesoderm Formation in the Drosophila Embryo
○ Neural Crest Delamination and Migration: Integrating Regulations of
Cell Interactions, Locomotion, Survival and Fate
○ Insect Flight Muscle Chemomechanics
○ The Role of Integrins in Cell Migration
○ Neural Crest Cell Plasticity: Size Matters
○ Neural Crest Stem Cells
○ Integrins: An Overview of Structural and Functional Aspects
○ An Evolutionary Perspective on Eukaryotic Membrane Trafficking
○ Slits and Their Receptors
○ Origins and Evolution of Cotranslational Transport to the ER
○ Origins and Evolution of the Actin Cytoskeleton
○ Comparison of Muscle Development in Drosophila and Vertebrates
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
○ The Genetic Regulation of Pigment Cell Development
 ○ Origin and Evolution of Self-Consumption: Autophagy
○ The Contribution of the Neural Crest to the Vertebrate Body
○ Dorsoventral Patterning of the Brain: A Comparative Approach
○ VEGF and Endothelial Guidance in Angiogenic Sprouting
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ CtBP and Hematopoietic Transcriptional Regulators
○ A New Member of the CtBP/BARS Family from Plants: Angustifolia
○ Simulation of Human Erythrocyte Metabolism
○ A Model Library of Bacterial Chemotaxis on E-Cell System
○ CtBP3/BARS and Membrane Fission
○ Hsp70-Mediated Protein Refolding in E-Cell
○ VEGF Receptor Signalling in Vertebrate Development
○ Vascular and Nonvascular Roles of VEGF in Bone Development
○ Morphogenesis of Epithelial Appendages: Variations on Top of a
Common Theme and Implications in Regeneration
○ Wnt/Wingless Signaling in Drosophila
○ The Role of Wnt Signaling in Vertebrate Head Induction and the
Organizer-Gradient Model Dualism
○ The Wnt Gene Family and the Evolutionary Conservation of Wnt
Expression
○ Secreted Antagonists/Modulators of Wnt Signaling
○ Patterning the Vertebrate Neural Plate by Wnt Signaling
○ Wnt/Wg and Heart Development
○ Wnt Signaling and Cell Migration
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
• DNA Surveillance and Repair
○ Roles of Poly(ADP-Ribose) Metabolism in the Regulation of Centrosome
Duplication and in the Maintenance of Neuronal Integrity
○ PARP and the Release of Apoptosis-Inducing Factor from Mitochondria
○ DNA Damage Signaling through Poly(ADP-Ribose)
○ Dynamic Interaction between PARP-1, PCNA and p21waf1/cip1
○ Parp and Epigenetic Regulation
○ Genome Degradation by DNAS1L3 Endonuclease: A Key PARP-1-
Regulated Event in Apoptosis
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
 ○ Role of Poly-ADP-Ribosylation in Cancer Development
○ The Fanconi Anemia/BRCA Pathway: FANCD2 at the Crossroad between
Repair and Checkpoint Responses to DNA Damage
○ Fluorescence-Signaling Nucleic Acid-Based Sensors
○ Trichothiodystrophy: A Disorder Highlighting the Crosstalk between
DNA Repair and Transcription
○ Mobile Genetic Elements of Malaria Vectors and Other Mosquitoes
○ Orchestration of Telomeres and DNA Repair Factors in Mammalian
Cells: Implications for Cancer and Ageing
○ Mechanisms of DNA Damage and Repair in Alzheimer Disease
○ Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks
in Mammalian Cells
• DNA Vaccines
○ The Introduction of New DNA Vaccines into Developing Countries
• Drug Design
○ A Conceptual Framework
○ Modeling Structure-Activity Relationships
○ Prediction of Drug-Like Properties
○ Evolutionary De Novo Design
○ Analysis of Chemical Space
• Endocrinology
○ Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated
Vesicle Exocytosis
○ Subcellular Compartmentalization of Insulin Signaling Processes and
GLUT4 Trafficking Events
○ Insulin Action in the Islet β-Cell
○ What Is Osteoporosis?
○ Insulin and IGF-I Receptor Structure and Binding Mechanism
○ Insulin Resistance
○ Insulin Action Gene Regulation
• Evolution
○ Ribozyme-Catalyzed Genetics
○ Origin and Evolution of DNA and DNA Replication Machineries
○ Life in a Tenuous Universe
○ The Frame for New Hypotheses of Evolution
○ Genomism and the Nature Trail
○ The Origin of Complexity
 ○ Our Young Planet: One Is Not a Choice
○ The Condensation of Life
○ The Origins of Species
○ Development of Biological Potential
○ Thoughts on Multi-Cellularity: How Nature Got Around Darwin
○ Natura non facit saltum (Nature does nothing in jumps)
○ The Invariance Concept
○ On the Evolution of Humans
○ Molecular Geneology
○ Experiments in Evolution
○ Quintessence
○ The Scope of Selection
• Extracellular Matrix
○ The Biogenesis and Cell Biology of Peroxisomes in Human Health and
Disease
○ Assembly of Microfibrils
• Gastroenterology
○ Nerve Regulation of Cholangiocyte Functions
○ Functional Heterogeneity of the Intrahepatic Biliary Epithelium
○ Bile Acid Interactions with Cholangiocytes
○ Estrogen Regulation of Cholangiocyte Proliferation
○ Nerve Regulation of Cholangiocyte Functions
○ Vascularization of the Intrahepatic Biliary Tree and Its Role in the
Regulation of Cholangiocyte Growth
○ Cytokine Regulation of Cholangiocyte Growth
○ Hyperemesis Gravidarum and Maternal Liver Disease
○ The Liver in Normal Pregnancy
○ Spectrum of Maternal Liver Disease
• Gene Expression
○ Stochastic Gene Expression: Dominance, Thresholds and Boundaries
○ Biological Consequences of Dosage Dependent Gene Regulation in
Multicellular Eukaryotes
○ GAGA: Structural Basis for Single Cys2His2 Zinc Finger-DNA Interaction
○ Identification of Mammalian E2F Regulatory Networks Using DNA
Microarray Hybridization Analyses
○ Homing Endonuclease I-TevI: An Atypical Zinc Finger with a Novel
Function
○ A Novel Test Statistic for the Identification of Local Selective Sweeps
Based on Microsatellite Gene Diversity
○ Periodic Selection and Ecological Diversity in Bacteria
○ LIM Domain and Its Binding to Target Proteins
○ MDM2: RING Finger Protein and Regulator of p53
○ Inferring Evolutionary History through Inter- and Intraspecific DNA
Sequence Comparison: The Drosophila janus and ocnus Genes
○ Selective Sweep in the Evolution of a New Sperm-Specific Gene in
Drosophila
○ The Superfamily of SCAN Domain Containing Zinc Finger Transcription
Factors
○ Putative Roles of kin17, a Mammalian Protein Binding Curved DNA, in
Transcription
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ A Zinc Ribbon Motif Is Essential for the Formation of Functional
Tetrameric Protein Kinase CK2
○ Rapid Evolution of Sex-related Genes: Sexual Conflict or Sex-specific
Adaptations?
○ Repression of Transcription by Curved DNA and Nucleoid Protein H-NS:
A Mode of Bacterial Gene Regulation
○ Curved DNA and Transcription in Eukaryotes
○ PNA and Oligonucleotide Inhibitors of Human Telomerase
○ Possible Roles of DNA Supercoiling in Transcription
○ MDM2: RING Finger Protein and Regulator of p53
○ Gene Regulatory Networks
○ Do DNA Triple Helices or Quadruplexes Have a Role in Transcription?
○ The Biology of Telomeres in Hypotrichous Ciliates
○ Scaling Laws in the Functional Content of Genomes: Fundamental
Constants of Evolution?
○ Regulation of Cardiomyocyte Proliferation and Apoptosis
○ Cell Cycle Reactivation in Skeletal Muscle and Other Terminally
Differentiated Cells
○ The Role of Unusual DNA Structures in Chromatin Organization for
Transcription
○ Molecular Mechanisms of Male Sex Determination: The Enigma of SRY
○ DNA: Alternative Conformations and Biology
 ○ Curved DNA and Prokaryotic Promoters: A Mechanism for Activation of
Transcription
○ Scale-Free Evolution: From Proteins to Organisms
○ Bioinformatics: Mystery, Astrology or Service Technology?
○ Extracting Information for Meaningful Function Inference Through Text-
Mining
○ Microarrays and Gene Regulation Networks in Yeast
○ Transcriptional Repression by the CtBP Corepressor in Drosophila
○ Structural Determinants of CtBP Function
○ Analytical Evolutionary Model for Protein Fold Occurrence in Genomes,
Accounting for the Effects of Gene Duplication, Deletion, Acquisition
and Selective Pressure
○ Power Law Correlations in DNA Sequences
○ Transcriptional Networks in Mammalian Gene Regulation
○ DNA Primer Extension by Telomerase
○ Transcriptional Profiling of the Hepatic Growth Response
○ Expression of Hox Genes in the Nervous System of Vertebrates
○ Telomeres: Guardians of Genomic Integrity or Double Agents of
Evolution?
○ Alternative Lengthening of Telomeres in Mammalian Cells
○ Evolution of Telomere Binding Proteins
○ Drosophila Telomeres: A Variation on the Telomerase Theme
○ Telomerase Activity as a Marker of Tumor Cell Survival to Evaluate
Sensitivity of Neoplastic Cells to Cancer Treatment
○ Myotonic Dystrophy: Discussion of Molecular Basis
○ Roles for TERT and Telomerase in Cell Differentiation and Apoptosis
○ Molecular Mechanisms of TRS Instability
○ Yeast Telomerases: Structure, Mechanisms and Regulation
○ The Significance of Quantitative Evaluation of Telomerase Activity and
hTERT mRNA Expression in Colorectal Cancers
○ Human, Mouse and Yeast Telomerase
○ Telomerase in Mesothelioma: Diagnostic and Therapeutic Applications
○ Telomerase Activity in Neuroblastomas: A New Molecular Marker for
Treatment Stratification and Prognostic Grouping
○ Telomerase and Radiosensitivity of Human Tumors
• Heart
○ Origin of Mechanotransduction: Stretch-Activated Ion Channels
 ○ Regional Differences and Variability in Left Ventricular Wall Motion
• Heat Shock Proteins
○ Assembly of Protein Aggregates in Neurodegeneration: Mechanisms
Linking the Ubiquitin/Proteasome Pathway and Chaperones
○ The Role of Heat Shock Proteins during Neurodegeneration in
Alzheimer's, Parkinson's and Huntington's Disease
• Hematology
○ Other Proteins and Their Interactions with FA Gene Products
○ The Genetic Basis of Fanconi Anemia
○ The FANCC Gene and Its Products
• Immunology
○ Animal Models of OXPHOS Disorders
○ Molecular Recognition of Haptens by T Cells: More Than One Way to
Tickle the Receptor
○ Phospholipases and Phagocytosis
○ IgA and Mucosal Homeostasis
○ Carbohydrate-Based Targets and Vehicles for Cancer and Infectious
Diseases Vaccines
○ Small GTP Binding Proteins and the Control of Phagocytic Uptake
○ Calcium Signaling During Phagocytosis
○ Regulation of Phagocytosis by FcγRIIb and Phosphatases
○ Adding Complexity to Phagocytic Signaling: Phagocytosis-Associated
Cell Responses and Phagocytic Efficiency
○ V(D)J Recombination: Of Mice and Sharks
○ Opioid Receptors on Peripheral Sensory Neurons
○ Morphological Correlates of Immune-Mediated Peripheral Opioid
Analgesia
○ Functional Evidence of Pain Control by the Immune System
○ Opioid Receptor Expression and Intracellular Signaling by Cells
Involved in Host Defense and Immunity
○ Experimental Evidence for Immunomodulatory Effects of Opioids
○ The Immune-Suppressive Effects of Pain
○ Lipoxins as an Immune-Escape Mechanism
○ Dynamic Aspects of TCRα Gene Recombination: Qualitative and
Quantitative Assessments of the TCRα Chain Repertoire in Man and
Mouse
○ Viral TNF Inhibitors as Potential Therapeutics
 ○ CD8 T-Cell Memory Differentiation during Acute and Chronic Viral
Infections
○ Chromatin Mechanisms Regulating Gene Expression In Health And
Disease
○ Earthworm Immunity
○ TRIM PROTEINS AS RING FINGER E3 UBIQUITIN LIGASES
○ REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for
Treatment of Mast-Cell Related Diseases?
○ GASTROPOD IMMUNOBIOLOGY
○ MAST CELLS AND IMMUNOREGULATION/IMMUNOMODULATION
• Infectious Disease
○ Everything (or Almost Everything) You Want to Know about Genetically
Modified Mosquitoes for Malaria Control but Are (Maybe) Afraid to Ask
○ Predicting the Spread of a Transgene in African Malaria Vector
Populations: Current Knowledge and Limitations
○ Invasion and Intracellular Survival by Toxoplasma
○ Negative Signaling and Modulation of Macrophage Function in
Trypanosoma cruzi Infection
○ Pro-Inflammatory Responses in Macrophages during Toxoplasma
gondii Infection
○ Avoidance of Innate Immune Mechanisms by the Protozoan Parasite,
Leishmania spp
○ Insect Population Suppression Using Engineered Insects
○ Current and Emerging Approaches to Studying Invasion in
Apicomplexan Parasites
• Ischemia-Reperfusion
○ Therapeutic Utilities of SOD Mimetics: Cancer, Radiotherapy and SOD
Mimetics
○ Development of Manganic Porphyrin Mimetics of Superoxide Dismutase
Activity
○ Role of Superoxide in Post-Ischemic Liver Injury
○ Evaluation of a Superoxide Dismutase Mimetic As an Adjunct to
Interleukin 2 Based Cancer Therapy
• Medical
○ STATs and Infection
○ JAK/STAT Pathway Signalling in Drosophila Melanogaster
○ Disease Transmission Models for Public Health Decision-Making:
Designing Intervention Strategies for Schistosoma japonicum
 ○ Parameter Estimation and Site-Specific Calibration of Disease
Transmission Models
• Molecular Biology
○ RNA Modification Subsystems in the SEED Database
○ KIR Genes and Their Role in Spondyloarthropathies
○ Antibiotic Resistance in Bacteria Caused by Modified Nucleosides in
23S Ribosomal RNA
○ The “PACE” Concept Pointed at New Key Proteins Involved in RNA
Metabolism
○ DNA Demethylation
○ Adhesion-Dependent Modulation of Macrophage K+ Channels
○ Pseudouridine Formation, the Most Common Transglycosylation in RNA
○ Folate-Dependent Thymidylate-Forming Enzymes: Parallels between
DNA and RNA Metabolic Enzymes and Evolutionary Implications
○ The Interplay between RNA and DNA Modifications: Back to the RNA
World
○ Deciphering the Complex Enzymatic Pathway for Biosynthesis of
Wyosine Derivatives in Anticodon of tRNAPhe
○ Nucleic Acids Are Not Boring Long Polymers of Only Four Types of
Nucleotides: A Guided Tour
○ Chemokine Binding Proteins Encoded by Pathogens
○ Boomerangs, Bananas and Blimps: Structure and Function of F-BAR
Domains in the Context of the BAR Domain Superfamily
○ Gas7
○ Enzyme-RNA Substrate Recognition in RNA-Modifying Enzymes
• Nanomedicine
○ STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?
• Neurodegenerative Disease
○ DSD-1-Proteoglycan/Phosphacan and Receptor Protein Tyrosine
Phosphatase-Beta Isoforms During Development and Regeneration of
Neural Tissues
○ Interleukin-10 and Psoriasis
○ Idiopathic Parkinson's Disease: Staging an α-Synucleinopathy with a
Predictable Pathoanatomy
○ Chromosome 1 and Other Hotspots for Parkinson's Disease Genes
○ Fibroblast Growth Factors
○ Neuronal Survival and Cell Death Signaling Pathways
○ Paved with Good Intentions: The Link between Cell Cycle and Cell
Death in the Mammalian Central Nervous System
 ○ α-Synuclein Physiology and Membrane Binding
○ Na Channels and Ca2+ Channels of the Cell Membrane as Targets of
Neuroprotective Substances
○ Heat Shock Proteins and Neuroprotection
○ Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain
Ischemia Following Delayed Intravenous Administration of
Neurotrophins
○ Neuroprotective Strategies in Animal and in Vitro Models of Neuronal
Damage: Ischemia and Stroke
○ Vascular Endothelial Growth Factor
○ Cell Cycle and Chromosome Segregation Defects in Alzheimer's
Disease
○ Neuroprotective Activity of Metabotropic Glutamate Receptor Ligands
○ Excitatory Amino Acid Neurotoxicity
○ Dopamine and Parkinson's Disease
○ Neurotrophins
○ Overview Αβ Metabolism: From Alzheimer Research to Brain Aging
Control
○ β-Secretase: Progress and Open Questions
○ APP α-Secretase, a Novel Target for Alzheimer Drug Therapy
○ γ-Secretase and Presenilin
○ Functional Roles of APP Secretases
○ Proteolytic Degradation of Αβ by Neprilysin and Other Peptidases
○ Αβ Degradation by Endothelin-Converting Enzymes
○ Ab Metabolism in Cholesterol-Enriched Membrane Microdomains
○ Amyloid β-Protein in Low-Density Membrane Domains
○ Transport-Clearance Hypothesis for Alzheimer's Disease and Potential
Therapeutic Implications
○ Potential Role of Endogenous and Exogenous Ab Binding Molecules in
Ab Clearance and Metabolism
○ Modulating Amyloid β Levels by Immunotherapy: A Potential
Therapeutic Strategy for the Prevention and Treatment of Alzheimer's
Disease
• Neuropharmacology
○ Diurnal 5-HT Production and Melatonin Formation
○ Pineal Gland and Cancer—An Epigenetic Approach to the Control of
Malignancy: Evaluation of the Role of Melatonin
○ Cell Adhesion Molecules
 ○ Risks of Chronic Hypnotic Use
○ Sleep Hippocampal Theta Rhythm and Sensory Processing
○ Cannabinoid Receptors and Signal Transduction
○ Protein Kinase A
○ A Comparison of Visual Analog Scale and Categorical Ratings in
Assessing the Patient's Estimate of Sleep Quality
• Neuroscience
○ Role of Semaphorins during Axon Growth and Guidance
• Nucleus
○ Riboflavin and Methylenetetrahydrofolate Reductase
○ Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR)
and Overview of Mutations/Polymorphisms
○ Methylenetetrahydrofolate Reductase Polymorphisms:
Pharmacogenetic Effects
○ Assays for Methylenetetrahydrofolate Reductase Polymorphisms
• Oncogenes
○ p53's Dilemma in Transcription: Analysis by Microarrays
○ TP63, TP73: The Guardian's Elder Brothers
○ Modes of p53 Interactions with DNA in the Chromatin Context
• Oncology
○ Fever, Pyrogens and Cancer
○ Gene Expression Profiling in Malignant Lymphomas
○ Cytoreduction, Peritonectomy and Hyperthermic Antiblastic Peritoneal
Perfusion for the Treatment of Peritoneal Carcinomatosis
○ Hyperthermic Isolated Limb Perfusion
○ Intracavitary Hyperthermic Perfusion
○ Locoregional Hyperthermia
○ Transcription of rDNA in the Yeast Saccharomyces cerevisiae
○ Pre-Ribosomal RNA Processing in Multicellular Organisms
○ PDGF Pathways and Growth of Basal Cell and Squamous Cell
Carcinomas
○ Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A
Radiation
○ Influence of Tumor Microenvironment on Thermoresponse: Biologic and
Clinical Implications
○ Physical Background and Technical Realizations of Hyperthermia
○ Effects of Local and Whole Body Hyperthermia on Immunity
 ○ Thermo-Chemo-Radiotherapy Association: Biological Rationale,
Preliminary Observations on Its Use on Malignant Brain Tumors
○ Molecular Mechanisms of ErbB2-Mediated Breast Cancer
Chemoresistance
○ Future Perspectives of Interstitial and Perfusional Hyperthermia
○ Roles of Multidrug Resistance Genes in Breast Cancer Chemoresistance
○ Insulin-Like Growth Factors and Breast Cancer Therapy
○ Novel Approaches for Chemosensitization of Breast Cancer Cells: The
E1A Story
○ Whole Body Hyperthermia at 43.5-44°C: Dreams or Reality?
○ Overview of Resistance to Systemic Therapy in Patients with Breast
Cancer
○ Microarrays for Cancer Diagnosis and Classification
○ Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines:
Clinical Results
○ Cellular Interactions in Nasopharyngeal Carcinomas
• Protein
○ Structure, Function and Assembly of Flagellar Axial Proteins
○ Implications of 3D Domain Swapping for Protein Folding, Misfolding and
Function
○ From Artificial Antibodies to Nanosprings:The Biophysical Properties of
Repeat Proteins
○ The Budding Yeast PCH/F-BAR Proteins
○ Gas7
○ The Coronin Family of Proteins
○ Diversity of WD-repeat Proteins
○ A Brief History of the Coronin Family
○ Phylogenetic, Structural and Functional Relationships between WD-and
Kelch-Repeat Proteins
○ The Role of Mammalian Coronins in Development and Disease
○ Invertebrate Coronins
○ Evolutionary and Functional Diversity of Coronin Proteins
○ Coronin: The Double-Edged Sword of Actin Dynamics
○ Coronin 1 in Innate Immunity
○ Molecular Phylogeny and Evolution of the Coronin Gene Family
○ Coronin Structure and Implications
○ Nuclear APC
 ○ Role of Mammalian Coronin 7 in the Biosynthetic Pathway
○ Post-Targeting Functions of Signal Peptides
• Reproductive Biology
○ Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor
Functions during Epidermal Development and Disease
○ Bi-Directional Cell Trafficking During Pregnancy: Long-term
Consequences for Human Health
○ Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular
Immunity
○ The Role of Corticotropin-Releasing Hormone (CRH) on Implantation
and Immunotolerance of the Fetus
○ Characterization of Human Dendritic Cells at the Maternal-Fetal
Interphase
○ Important Role of Shh Controlling Gli3 Functions During the Dorsal-
Ventral Patterning of the Telencephalon
○ Spatial and Temporal Regulation of Hair Follicle Progenitors by
Hedgehog Signalling
○ MHC Molecules of the Preimplantation Embryo and Trophoblast
○ The Role of Regulatory T Cells in Materno-Fetal Tolerance
○ Cytogenetics of Human Sperm
○ Preimplantation Genetic Diagnosis (PGD): Screening for Aneuploidy in
Human Oocytes and Polar Bodies
○ Proteases and Their Cognate Inhibitors of the Serine and
Metalloprotease Subclasses, in Testicular Physiology
○ Antioxidant Systems and Oxidative Stress in the Testes
• RNA
○ Protein-Switched Ribozymes
○ Proteins Carrying One or More Unnatural Amino Acids
○ Therapies of Nonsense-Associated Diseases
○ All Termination Events Are Not Equal: Premature Termination in Yeast
Is Aberrant and Triggers NMD
○ Role of SMG-1-mediated Phosphorylation of Upf1 in NMD
○ NMD in Drosophila: A Snapshot into the Evolution of a Conserved
mRNA Surveillance Pathway
○ The snoRNPs and Related Machines: Ancient Devices That Mediate
Maturation of rRNA and Other RNAs
○ Trytophanyl-tRNA Synthetases
○ Tyrosyl-tRNA Synthetases
○ Cytokines, Chemokines and Their Receptors
○ Valyl-tRNA Synthetases
○ Protein-Induced RNA Switches in Nature
○ Class I Lysyl-tRNA Synthetases
○ Glutaminyl-tRNA Synthetases
○ Asparaginyl-tRNA Synthetases
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Aminoacyl-tRNA Synthetases and Disease
○ Human Upf Proteins in NMD
○ Phenylalanyl-tRNA Synthetases
○ Regulation of Gene Expression by Coupling of Alternative Splicing and
NMD
○ NMD and Human Disease
○ Polyadenylation and Degradation of RNA in Prokaryotes
○ Regulation of the Expression of Aminoacyl-tRNA Synthetases and
Translation Factors
○ Conformational Dynamics within the Ribosome
○ Tests of a Stereochemical Genetic Code
○ Evasion of Phagosome Lysosome Fusion and Establishment of a
Replicative Organelle by the Intracellular Pathogen Legionella
pneumophila
○ The End in Sight: Poly(A), Translation and mRNA Stability in Eukaryotes
○ Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized
for Gene Expression
○ Mechanism of Translation Initiation in Eukaryotes
○ A Prelude to Translational (Re)Initiation
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Mitochondrial Aminoacyl-tRNA Synthetases
○ Transfer RNA Structure and Identity
○ Post-Transcriptional Gene Silencing in Plants
○ Turnover of Mature miRNAs and siRNAs in Plants and Algae
○ miRNAs need a Trim Regulation of miRNA Activity by Trim-NHL Proteins
○ Structural Components and Architectures of RNA Exosomes
○ C. ELEGANS STAR PROTEINS, GLD-1 AND ASD-2, REGULATE SPECIFIC
RNA TARGETS TO CONTROL DEVELOPMENT
• Signal Transduction
○ Genetic Susceptibility to Infectious Diseases Linked to NRAMP1 Gene in
Farm Animals
○ FasL-Independent Activation of Fas
○ Plant Metal Transporters with Homology to Proteins of the NRAMP
Family
○ Regulation of Bacterial MntH Genes
○ Physiological Roles and Mechanisms of Signaling by TRAF2 and TRAF5
○ Metal-ion Transporters— From Yeast to Human Diseases
○ The Function of Toll-Like Receptors
○ Regulation of the RhoGTPases by RhoGDI
○ How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-
GLI Signaling as Anti-Cancer Therapy?
○ Rho Family GTPases and Cellular Transformation
○ GLI Genes and Their Targets in Epidermal Development and Disease
○ Regulation of Cell Motility by Abl Family Kinases
○ The Patched Receptor: Switching On/Off the Hedgehog Signaling
Pathway
○ Shh Expression in Pulmonary Injury and Disease
○ Regulation of Cell Adhesion Responses by Abl Family Kinases
○ Abl Family Kinases in Mammalian Development
○ Abl and Cell Death
○ Mechanisms of Activation of Abl Family Kinases
○ Regulation of Cytoskeletal Dynamics and Cell Morphogenesis by Abl
Family Kinases
○ TRAFs in RANK Signaling
○ Abelson Family Protein Tyrosine Kinases and the Formation of Neuronal
Connectivity
○ The LTβR Signaling Pathway
○ Neurons, Neurotrophins and Ceramide Signaling: Do Domains and
Pores Contribute to the Dichotomy?
○ The Role of Serine/Threonine Protein Phosphatases in Ceramide
Signaling
○ Chaperone Effects on Prion and Nonprion Aggregates
○ Insights into the Modulation of Ceramide Metabolism by Naturally
Occurring and Synthetic Sphingolipid Analogs as Monitored by
Electrospray Tandem Mass Spectrometry
○ Ceramide Glycosylation and Chemotherapy Resistance
 ○ S-Modulin
○ Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by
Divalent Cations and Polyamines
○ Target Recognition of Guanylate Cyclase by Guanylate Cyclase-
Activating Proteins
○ Centrins, a Novel Group of Ca2+-Binding Proteins in Vertebrate
Photoreceptor Cells
○ The TRP Calcium Channel and Retinal Degeneration
○ Ca2+-dependent Control of Rhodopsin Phosphorylation: Recoverin and
Rhodopsin Kinase
○ The Complex of cGMP-gated Channel and Na/Ca2+, K Exchanger in Rod
Photoreceptors
○ RGS9-1 Phosphorylation and Ca2+
○ Ceramide in the Regulation of Neuronal Development: Two Faces of a
Lipid
○ Therapeutic Implications of Ceramide-Regulated Signaling Cascades
○ Photoreceptor Degeneration and Ca2+ Influx through Light-Activated
Channels of Drosophila
○ Regulation of the Rod Photoreceptor Cyclic Nucleotide-Gated Channel
○ Mouse Models to Study GCAP Functions in Intact Photoreceptors
○ Using Mutant Mice to Study the Role of Voltage-Gated Calcium
Channels in the Retina
○ Calcium Channels at the Photoreceptor Synapse
○ Biosynthesis of Sphingolipids in Plants (and Some of Their Functions)
○ Ceramide 1-Phosphate in Cell Survival and Inflammatory Signaling
• Stem Cells
○ Knockout Mouse Models of Cytokine Action in Hematopoietic Stem Cell
Regulation
○ Cytokines, Receptors and Signalling Pathways Involved in Macrophage
and Dendritic Cell Development
• Tissue Engineering
○ Scleroderma Lung Fibroblasts: Contractility and Connective Tissue
Growth Factor
○ Repair of Osteochondral Lesions
○ Regulatory Issues: Down to the Bare Bones
○ Anatomy and Physiology of the Spinal Cord
○ Encouraging Regeneration of Host Neurones: The Use of Peripheral
Nerve Bridges, Glial Cells or Biomaterials
○ Replacement of Specific Neuronal Populations in the Spinal Cord
 ○ Replacement of Specific Populations of Cells: Glial Cell Transplantation
into the Spinal Cord
○ In Vitro Endothelialization: Its Contribution Towards an Ideal Vascular
Replacement
○ Biocompatibility of Polyurethanes
○ Tissue Repair in Asthma: The Origin of Airway Subepithelial Fibroblasts
and Myofibroblasts
○ Functional Assessment of Fibroblast Heterogeneity by the Cell-Surface
Glycoprotein Thy-1
○ Pro-Invasive Molecular Cross-Signaling between Cancer Cells and
Myofibroblasts
○ Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinase and
Matrix Turnover and the Fate of Hepatic Stellate Cells
• Transplant
○ Polyomavirus Allograft Nephropathy: Clinico-Pathological Correlations
○ Metabolic Management
• Vaccines
○ Immune Responses to DNA Vaccines: Induction of CD8 T Cells
○ Neisseria meningitidis Vaccines
○ DNA Vaccines against Bacterial Pathogens
○ Dendritic Cells: Important Adjuvants During DNA Vaccination
• Viruses
○ A Role for Chemokine Activity in Alphavirus Pathogenesis: Evidence
from the Analysis of Polyarthritis and Myalgia Post-Ross River Virus
Infection
○ Evolutionary Aspects of Human Endogenous Retroviral Sequences
(HERVs) and Disease
○ Structure and Replication of Hepatitis Delta Virus RNA
○ Hepatitis Delta Virus RNA Editing
○ Hepatitis Delta Antigen and RNA Polymerase II
○ Transforming Activities of JC Virus Early Proteins
○ DNA Packaging by Bacteriophage P22
○ Regulation of T Cell Immunity by OX40 and OX40L
○ BK Virus, JC Virus and Simian Virus 40 Infection in Humans, and
Association with Human Tumors
○ The ø29 DNA Packaging Motor: Seeking the Mechanism
○ Phylogenomics and Molecular Evolution of Polyomaviruses
○ Urine Cytology Findings of Polyomavirus Infections
 ○ Immunity and Autoimmunity Induced by Polyomaviruses: Clinical,
Experimental and Theoretical Aspects
○ Soluble Chemokine Binding Proteins Encoded by Viruses
○ Bacteriophage Lambda Terminase and the Mechanism of Viral DNA
Packaging
○ DNA Packaging in Bacteriophage T4
○ Bacteriophage SPP1 DNA Packaging
○ Polyomavirus-associated Nephropathy in Renal Transplantation: Critical
Issues of Screening and Management
○ Entry of Herpesviruses into Cells: The Enigma Variations
< PrevNext >

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.
Bookshelf ID: NBK6193

Structure and Function of the Dystrophin-Glycoprotein

Complex
James M. Ervasti.
Introduction
Go to:

• Top▲
Duchenne muscular dystrophy (DMD) is the most prevalent and severe form of human muscular
dystrophy. While clinical descriptions of DMD date back to the 1850's, over 100 years passed
before evidence suggested that the muscle cell plasma membrane, or sarcolemma, is
compromised in DMD muscle. The molecular basis for DMD and its associated sarcolemmal
instability became more clear with landmark studies published in the mid-to-late 1980's which
identified the gene defective in DMD.1 The DMD locus spans over 2.5 million bases
distinguishing it as the largest gene in the human genome. The array of transcripts expressed
from the DMD gene is complex due to the presence of multiple promoters and alternative
splicing. The largest transcripts encode a four-domain protein with a predicted molecular weight
of 427,000, named dystrophin. Dystrophin is the predominant DMD transcript expressed in
striated muscle and DMD gene mutations, deletions or duplications most frequently result in a
loss of dystrophin expression in muscle of patients afflicted with DMD. Based on its localization
to the cytoplasmic face of the sarcolemma and sequence similarity with domains/motifs common
to proteins of the actin-based cytoskeleton, dystrophin was hypothesized early on to play a
structural role in anchoring the sarcolemma to the underlying cytoskeleton and protect the
sarcolemma against stress imposed during muscle contraction or stretch. Biochemical studies
aimed at confirming the hypothesized structure and function of dystrophin revealed its tight
association with a multi-subunit complex, the so-named dystrophin-glycoprotein complex. Since
its description, the dystrophin-glycoprotein complex has emerged as an important structural unit
of muscle and also as a critical nexus for understanding muscular dystrophies arising from
defects in several distinct genes.
Initial Isolation and Characterization of the Dystrophin-
Glycoprotein Complex
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• Top▲
Following close behind the identification of dystrophin as the protein missing from DMD
muscle, the laboratory of Kevin Campbell demonstrated that dystrophin could be solubilized
from the membrane vesicle fraction of skeletal muscle homogenates using the detergent digitonin
and dramatically enriched by wheat germ agglutinin chromatography.2 Given that the primary
sequence contained no hydrophobic stretches to directly anchor dystrophin within the
sarcolemma, it seemed most likely that dystrophin indirectly bound to wheat germ agglutinin
through association with a membrane glycoprotein embedded in the sarcolemma and this idea
was confirmed by experiments showing that dystrophin binding to wheat germ agglutinin was
disrupted by chaotropic agents.2 While anion-exchange chromatography further amplified and
purified dystrophin over wheat germ agglutinin chromatography alone, numerous proteins
remained in the peak dystrophin fractions and lectin blotting minimally revealed 12 copurifying
glycoproteins as potential molecular partners for dystrophin.2 Sucrose gradient centrifugation
further resolved potential candidates to 9 proteins stained by Coomassie blue that were shown to
strictly cosediment with dystrophin (Fig. 1): a singlet of 88,000, a triplet of 59,000, a singlet of
50,000, a doublet of 43,000, a singlet of 35,000 (but present at a molar ratio of ˜2:1 relative to
dystrophin) and a singlet of 25,000 apparent Mr. Lectin blotting identified the 50,000, 43,000 and
35,000 species as glycoproteins and further revealed a broad band with an apparent molecular
weight of 156,000.3 While the 156,000 Mr protein was poorly stained by Coomassie blue, its
strong staining by wheat germ agglutinin and strict cosedimentation with dystrophin nonetheless
elevated its candidacy as a sarcolemmal glycoprotein receptor for dystrophin.3 Thus, the list of
potential dystrophin-associated proteins was narrowed down to 10 distinct Mr proteins, 5 of
which were glycosylated.

Figure 1
Protein Constituents of the Dystrophin-Glycoprotein Complex. Shown on the left is a Coomassie
blue-stained SDS-polyacrylamide gel loaded with dystrophin-glycoprotein complex purified
from rabbit skeletal muscle. Molecular weight standards are indicated (more...)
Protein Constituents of the Dystrophin-Glycoprotein Complex. Shown on the left is a Coomassie
blue-stained SDS-polyacrylamide gel loaded with dystrophin-glycoprotein complex purified
from rabbit skeletal muscle. Molecular weight standards are indicated on the left while the
molecular weights of each dystrophin-associated protein (DAP) or glycoprotein (DAG) are
indicated on the right. Also shown are western blots containing electrophoretically-resolved
dystrophin-glycoprotein complex that was enriched from digitonin-solubilized mouse skeletal
muscle by wheat germ agglutinin chromatography. Western blots were stained with antibodies
specific for dystrophin (DYS), α- and β-dystroglycan (DG), α-dystrobrevin (α-Db), syntrophin
(SYN), α-, β-, γ- and δ-sarcoglycans (SG) and sarcospan (SPN).
Importantly, the Campbell lab was simultaneously pursuing a long-term project aimed at
generating new monoclonal antibodies to calcium channels expressed in muscle. Since several
calcium channel subunits were known to be glycosylated, wheat germ agglutinin-enriched
fractions from detergent solubilized muscle membranes were used to immunize mice and screen
hybridomas. Screening positive clones against dystrophin-enriched preparations yielded
monoclonal antibodies to dystrophin, the 156,000 and 50,000 Mr dystrophin associated
glycoproteins. 3 The new antibodies were instrumental in confirming through
coimmunoprecipitation experiments the tight association of proteins that cosedimented with
dystrophin as well as their colocalization with dystrophin at the sarcolemma.3-5 Moreover, the
monoclonal antibodies were critical in demonstrating that the abundance of the 156,000 and
50,000 Mr dystrophin-associated glycoproteins was dramatically reduced in DMD muscle.3,6,7
Since these proteins colocalized with dystrophin in situ, copurified with dystrophin in
stoichiometric amounts even after several distinct protein purification methodologies, and were
diminished in dystrophin-deficient muscle, it was concluded that dystrophin was part of a large,
hetero-oligomeric complex that may serve to stabilize the sarcolemma. Because several
constituents were glycosylated and exploitation of this characteristic was so important in their
isolation, the assembly of proteins associated with dystrophin was named the dystrophin-
glycoprotein complex.
Additional biochemical analyses identified the 156,000 glycoprotein and 59,000 Mr triplet as
peripheral membrane proteins5 while the 50,000, 43,000, 35,000 and 25,000 Mr species behaved
as a subcomplex of integral membrane proteins.5,8 Based on its extensive glycosylation5,9 and
peripheral membrane association, the 156,000 Mr dystrophin-associated glycoprotein was
hypothesized to reside on the extracellular face of the sarcolemma and possibly function as a
receptor for a component of the extracellular matrix. These hypotheses were born out with the
cloning/sequencing of the gene encoding the 156,000 dystrophin-associated glycoprotein, which
is expressed from a single transcript along with one of the 43,000 Mr dystrophin-associated
glycoproteins.6 The propeptide is proteolytically processed into a wholly extracellular 156,000
subunit and a 43,000 Mr single-pass transmembrane subunit. Based on its extensive
glycosylation and association with dystrophin, the 156,000 and 43,000 Mr subunits were
renamed α- and β-dystroglycan, respectively. A screen of known extracellular matrix molecules
for skeletal muscle α-dystroglycan binding activity identified laminin as the first extracellular
ligand for α-dystroglycan.6,9 Laminin-Sepharose pull-down of the entire dystrophin complex
definitively demonstrated that α-dystroglycan was a stoichiometric component of the complex.9
These results also led to the hypothesis that the dystrophin-glycoprotein complex may play a role
in muscle cell adhesion to the basal lamina.
Working independently, Ozawa and colleagues corroborated10-12 many of the key findings first
reported by the Campbell laboratory and they made some important original contributions in
elucidating several of the protein-protein interactions within the complex (discussed below).
However, Ozawa and colleagues strongly disputed two important conclusions of Campbell's
group. First, they initially dismissed α-dystroglycan as an important component of the
dystrophin-glycoprotein complex because it could not be stained by Coomassie blue.13 Ozawa
and colleagues also strongly contested the initial identification of the 59,000 Mr α-
dystrobrevin/syntrophin triplet as cytoplasmic peripheral membrane proteins because their
experiments led them to conclude that one of the proteins was a transmembrane glycoprotein. 12
In subsequent work,14 it is clear that Ozawa and colleagues ultimately concurred that α-
dystroglycan is an important component of the complex and that syntrophins are nonglycosylated
cytoplasmic proteins. Using limited proteolysis, wheat germ agglutinin chromatography and an
array of site-specific antibodies, Ozawa and colleagues first demonstrated that the cysteine-rich
and first half of the C-terminal domains of dystrophin were important for its binding to the
glycoprotein complex.11 By blot overlay assay, they showed that β-dystroglycan, and the 88,000
and 59,000 Mr dystrophin-associated proteins (α-dystrobrevins and syntrophins) directly bound
the cysteine-rich and/or C-terminal domains of dystrophin,15 despite failing to reconcile their
prior crosslinking studies where they concluded that the 50,000 and 35,000 Mr dystrophin-
associated glycoproteins were directly associated with dystrophin and most important in
anchoring it to the sarcolemma.10 Ozawa and colleagues also more conclusively showed16 that the
dystrophin-glycoprotein complex could be dissociated into 3 sub-complexes consisting of α- and
β-dystroglycan (dystroglycan complex), the 50,000, 43,000, and 35,000 Mr dystrophin-associated
glycoproteins (sarcoglycan complex), dystrophin plus the 87,000 and 59,000 Mr dystrophin-
associated proteins (dystrophin/dystrobrevin/syntrophin complex). However, it bears noting that
several studies predating the work of Ozawa and colleagues reported data suggesting resolution
of sub-complexes with similar molecular compositions. 5,8,17,18
The largely biochemical studies described above suggested that the dystrophin-glycoprotein
complex may function to physically couple the sarcolemmal cytoskeleton with the extracellular
matrix (Fig. 2) and that loss of this structural linkage may render the sarcolemma more
susceptible to damage when exposed to mechanical stress. The purified dystrophin-glycoprotein
complex also provided a substrate for peptide sequencing and antibody production which yielded
new probes important in the identification of genes encoding all dystrophin associated teins and
elucidation of their respective roles in Duchenne and other forms of muscular dystrophy.
Notably, the genes encoding several dystrophin-associated proteins cause forms of muscular
dystrophy when mutated in humans or when knocked out in mice. Since dystrophin and its
associated proteins are each a story in and of themselves, I will leave their detailed discussions to
be elaborated in the specific chapters that follow. Below I will summarize the large body of
evidence supporting an important mechanical role for the dystrophin-glycoprotein complex and
then discuss its function within the larger protein network of skeletal muscle. Finally, I will
propose an engineering design analogy that I believe best fits existing data.

Figure 2
Model of the Dystrophin-Glycoprotein Complex. Dystrophin is thought to physically couple the
sarcolemma with the costameric cytoskeleton (see Fig. 3) through lateral association of its N-
terminal and rod domains with cytoplasmic γ-actin filaments (more...)
Model of the Dystrophin-Glycoprotein Complex. Dystrophin is thought to physically couple the
sarcolemma with the costameric cytoskeleton (see Fig. 3) through lateral association of its N-
terminal and rod domains with cytoplasmic γ-actin filaments and through direct binding of its
cysteine-rich domain to the β-subunit of the dystroglycan complex. Oligosaccharides present on
α-dystroglycan are important for its binding to laminin-2 of the extracellular matrix. The
sarcoglycan-sarcospan complex is thought to strengthen the noncovalent binding of dystrophin
and α-dystroglycan with β-dystroglycan. α-Dystrobrevin appears to couple dystrophin with the
sarcoglycan-sarcospan complex and also link the dystrophin-glycoprotein complex with the
intermediate filament cytoskeleton (see Fig. 4). Two syntrophin molecules are anchored through
homologous binding sites present in the C-terminal domains of dystrophin and α-dystrobrevin.
Syntrophins are thought to serve as adaptor molecules that localize signaling molecules near the
sarcolemma (see Fig. 4). Redrawn from.95
In Support of a Mechanical Function for the Dystrophin-
Glycoprotein Complex
Go to:

• Top▲
Within skeletal myofibers, dystrophin is enriched in a discrete, rib-like lattice termed
costameres.19,20 Costameres are protein assemblies that circumferentially align in register with the
Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the
sarcolemma in striated muscle cells (Fig. 3). A variety of data indicate that costameres are a
striated muscle-specific elaboration of the focal adhesions expressed by nonmuscle cells.21
Classical experiments by Street22 and the Sangers23 suggest that costameres function to laterally
transmit contractile forces from sarcomeres across the sarcolemma to the extracellular matrix and
ultimately to neighboring muscle cells. Lateral transmission of contractile force would be useful
for maintaining uniform sarcomere length between adjacent actively contracting and resting
muscle cells comprising different motor units within a skeletal muscle. It is also logical that the
sites of lateral force transmission across the sarcolemma would be mechanically fortified to
minimize stress imposed on the relatively labile lipid bilayer. Other results suggest that
costameres may also coordinate an organized folding, or “festooning” of the sarcolemma,22,24
which again may minimize stress experienced by the sarcolemmal bilayer during forceful muscle
contraction or stretch. Thus, in support of its hypothesized mechanical function, dystrophin is
enriched within a structure (the costamere) that likely transmits mechanical force to and through
the sarcolemma.

Figure 3
The costameric cytoskeleton of striated muscle. Dystrophin is enriched at costameres, protein
assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and
physically couple force-generating sarcomeres with the sarcolemma. (more...)
The costameric cytoskeleton of striated muscle. Dystrophin is enriched at costameres, protein
assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and
physically couple force-generating sarcomeres with the sarcolemma. Redrawn from 21
Consistent with its enrichment at costameres in normal muscle, the absence of dystrophin in
humans and mice leads to a disorganized costameric lattice.19,25-28 Extensive data consistently
report that the dystrophin-deficient sarcolemma is exceedingly fragile29-31 resulting in
dramatically increased movement of membrane impermeant molecules across the sarcolemma of
dystrophin-deficient muscle.30-42 Both necrosis and sarcolemmal permeability of dystrophin-
deficient muscle are exacerbated by physical exercise and improved by muscle immobilization.
33,35,39,42-45
Physiological studies have demonstrated that force production by dystrophin-deficient
muscle is significantly decreased when normalized against muscle cross-sectional area.40,41,46-59
Interestingly, force output by dystrophin-deficient muscle is hypersensitive to lengthening, or
eccentric contraction60,61 and the force decrement exhibited by dystrophin-deficient muscle
undergoing eccentric contraction positively correlates with acutely increased sarcolemmal
permeability.40,41,53-55,59-63 Immunofluorescence analysis of mechanically peeled sarcolemma has
demonstrated that dystrophin at costameres is tightly attached to the sarcolemma20 and its
presence is necessary for strong coupling between the sarcolemma and costameric actin
filaments comprised of cytoplasmic γ-actin.64 Transgenic overexpression of the dystrophin
homologue utrophin, or a dystrophin construct retaining the β-dystroglycan binding site and one
actin binding domain is sufficient to restore coupling between the sarcolemma and costameric
actin and rescue the sarcolemmal permeability defects accompanying dystrophin deficiency.65,66
Dystrophin is also enriched in costameres of cardiac muscle.67 Like skeletal muscle, dystrophin-
deficient cardiac myocytes are abnormally vulnerable to mechanical stress-induced contractile
failure and injury.68,69 Finally, knockout of the dystroglycan or sarcoglycan complexes also
causes muscular dystrophy that is accompanied by defects in sarcolemmal integrity.70-79 When
taken together, the above studies provide compelling evidence that the dystrophin-glycoprotein
complex mainly functions to anchor the sarcolemma to costameres and stabilize it against the
mechanical forces transduced through costameres during muscle contraction or stretch.
Expanding beyond the Dystrophin-Glycoprotein Complex
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• Top▲
Since its initial description in 1990, many additional proteins have been shown to interact with
different dystrophin-glycoprotein complex components (Fig. 4). Once the laminin α-chain G-
domain was identified as the binding site for α-dystroglycan,80 several other proteins containing
homologous G-domain modules were interrogated and shown to bind α-dystroglycan with high
affinity. The current list of such proteins includes agrins,81-84 neurexins85 and perlecan.86,87 Like
laminins, these proteins all bind to α-dystroglycan in a manner dependent on its oligosaccharide
modifications.88 In contrast, the chondroitin sulfate chains of the proteoglycan biglycan have
been shown to mediate its binding to the core protein of α-dystroglycan.89 While the functional
significance of α-dystroglycan binding to several different extracellular matrix molecules is not
fully clear, the results suggest that the dystroglycan complex may serve multiple roles that vary
with the extracellular ligand to which it is bound. That agrins, neurexins and perlecan have all
been implicated in various aspects of synapse formation or function.90 further suggests
participation by the dystroglycan complex in this process.
Figure 4
The Protein Interacting Network of the Dystrophin-Glycoprotein Complex. AQP4, aquaporin 4;
Cav-3, caveolin-3; nNOS, neuronal nitric oxide synthase; SAPK3, stress-activated protein kinase
3 For a full list of supporting references, refer to the supplementary (more...)
The Protein Interacting Network of the Dystrophin-Glycoprotein Complex. AQP4, aquaporin 4;
Cav-3, caveolin-3; nNOS, neuronal nitric oxide synthase; SAPK3, stress-activated protein kinase
3 For a full list of supporting references, refer to the supplementary information in 21 from
which this figure was redrawn.
Based on its sequence similarity with the calponin homology actin binding domains of β-spectrin
and α-actinin, the N-terminal domain of dystrophin was hypothesized to bind actin filaments.
Indeed, recombinant proteins encoding the dystrophin N-terminal domain do bind actin
filaments,91 but with relatively low affinity.92 In contrast, purified dystrophin-glycoprotein
complex bound actin filaments with substantially higher affinity compared to the isolated amino-
terminal domain. The stoichiometry of binding however, suggested a more extensive lateral
association between dystrophin and actin filaments than could be explained by actin binding
solely through the N-terminal domain alone.93 Mapping of the actin binding sites in dystrophin
through F-actin cosedimentation of fragments after limited proteolysis led to the identification of
a second actin binding site situated in the middle third of the dystrophin rod domain.93 The
spectrin-like repeats in this novel actin binding site were found to carry an excess of basic amino
acid residues and were shown to bind acidic actin filaments largely through electrostatic
interaction.94 Because the middle rod actin binding site of dystrophin was separated from the
amino-terminal actin binding domain by ˜1200 amino acids, the two sites were proposed to act in
concert to effect an extended lateral association that could account for the measured
stoichiometry of binding. In addition, the dystrophin-glycoprotein complex was shown to slow
depolymerization of actin filaments in vitro.93,95 These data supported a novel actin filament side-
binding model for dystrophin and are entirely consistent with a role for the dystrophin-
glycoprotein complex in mechanically coupling the sarcolemma with actin filaments of the
costameric cytoskeleton.64
The development of two-hybrid methodologies for the identification of protein-protein
interactions has led to the discovery of several proteins that interact with the dystrophin-
glycoprotein complex. Two-hybrid screens using α-dystrobrevin as bait identified several novel
proteins.96-98 Two of these proteins, synemin/desmuslin98 and syncoilin,99 are structurally related
to intermediate filament proteins and interact with the classical intermediate filament protein
desmin. Interestingly, mice knocked out for either α-dystrobrevin100 or desmin101,102 exhibit
skeletal and cardiomyopathy, which suggests that mechanical coupling of the dystrophin-
glycoprotein complex to the intermediate filament cytoskeleton is necessary for normal muscle
function (see Chapter 5). Two hybrid screens using the cytoplasmic domains of sarcoglycans
identified a skeletal muscle-specific form of filamin (γ-filamin) as a sarcoglycan interacting
protein.103 Like dystrophin, filamin contains an N-terminal calponin homology actin binding
domain and a large number of repeated motifs, although the repeats in filamin differ in structure
from those in dystrophin. Interestingly, filamin A is recruited to focal adhesions of nonmuscle
cells in response to local mechanical stress applied via collagen-coated magnetic beads.104 Since
γ-filamin is upregulated and recruited to the sarcolemma in dystrophin-deficient muscle,103 it is
tempt- ing to speculate that the dystrophin-deficient costamere may “sense” increased
mechanical stress and attempt to compensate by recruitment of filamin. In addition to γ-filamin,
several more actin binding proteins of costameres are upregulated in dystrophin-deficient muscle
including the cytolinker plectin,105 the integrin-associated proteins talin and vinculin106 and the
laminin receptor α7β1 integrin.107,108 While not normally present at costameres, the dystrophin
homologue utrophin is upregulated and recruited to costameres in dystrophin-deficient
muscle.64,65 Based on the protein interaction network illustrated in (Fig. 4), it seems most
reasonable that all of these structural proteins are upregulated by the dystrophin-deficient muscle
cell in an attempt to compensate for the absence of dystrophin by fortifying the weakened
costamere through the recruitment of parallel mechanical linkages. Because dystrophy persists,
these parallel linkages are either not completely redundant with the dystrophin-glycoprotein
complex, or the compensatory upregulation/recruitment is incomplete. In support of the latter
possibility, transgenic overexpression of utrophin37,53,54 or α7 integrin109 has been shown to further
compensate for dystrophin deficiency. Thus, many of the proteins found to interact with the
dystrophin-glycoprotein complex, or upregulated in its absence, appear to couple the complex
with other structural elements of muscle, or form parallel mechanical links between the
sarcolemma and myofibrillar apparatus. As such, these findings further reinforce an important
mechanical function for the dystrophin-glycoprotein complex.
An Engineering Design Analogy
Go to:

• Top▲
In many respects, the bulk of experimental data indicate that the dystrophin-glycoprotein
complex functions in a manner analogous to the two-by-four (˜2 inch × 4 inch) timbers used to
frame the typical American stick house. The architect utilizes two-by-fours as one structural
element of a sturdy support matrix (ie., the costamere) intended to securely hold in place
weatherproof siding and shingles (ie., the sarcolemma) as well as doors and windows (ie., ion
channels and pumps) that allow for controlled movement of occupants, air and light both into
and out of the house. When built to the architect's specifications, the house (or normal muscle
cell) can withstand the stress imposed on it by extremes in weather such as high winds or heavy
snowfall (or muscle contraction). If, however, the house is built during a shortage of two-by-
fours (ie., the dystrophin-deficient muscle cell), the carpenter may be forced to substitute two-by-
two timbers instead (ie., compensatory upregulation of partially redundant structural proteins).
Such an alteration from original design may indeed allow the carpenter to construct a house that
stands in calm weather. Conversely, the compromised structure may distort sufficiently under the
force of gravity to cause doors and windows to stick or not close tightly. Moreover, the house
built with substandard structural elements is certainly less likely to remain intact when more
severe weather strikes.
Up to this point, the dystrophin-glycoprotein complex as two-by-four analogy has not taken into
account that several interacting proteins suggest additional roles for the dystrophin-glycoprotein
complex in organizing molecules involved in cellular signaling (Fig. 4). For example, α-
syntrophin anchors neuronal nitric oxide synthase to the sarcolemma,110 which is necessary to
properly regulate vascular perfusion in active muscle.111,112 Other data indicate that MAP kinase
signaling pathways are perturbed in dystrophin-deficient muscle.113-115 Because the putative
role(s) for the dystrophin-glycoprotein complex in cell signaling will no doubt be elaborated in
subsequent chapters, the reader may be left wondering whether and how a role in signaling fits
with its well-supported mechanical function. However, I believe the dystrophin-glycoprotein
complex as two-by-four analogy fits well with its role in anchoring signaling molecules and also
can explain the signaling perturbations observed in dystrophin-deficient muscle. While the
architect clearly intended the two-by-fours as structural support for the weather-proofing and
controlled entry components of the house, this primary function does not prevent the electrician,
plumber, telephone and cable television installers from subsequently utilizing the two-by-four
framework as a support to route and organize additional regulatory and communication systems
(ie., cell signaling pathways) that further enhance functionality of the house. These additional
systems would very reasonably be expected to malfunction in a house constructed of substandard
structural components (ie., two-by-twos instead of two-by-fours) as a secondary consequence of
its distortion under gravity or when challenged by more stringent weather conditions.
Alternatively, one could as reasonably argue that mechanical distortion of the structurally weak
two-by-two framework house may cause a short in the electrical system (ie., altered cell
signaling) that in turn destroys the house by catastrophic fire (ie., apoptosis). In either case, I
believe the architect could successfully argue that compromised mechanical integrity precipitated
destruction of the house (and that was not his, but the carpenter's fault!). The mere association of
signaling molecules with the dystrophin-glycoprotein complex and perturbations of signal
transduction pathways in dystrophin-deficient muscle are not sufficient evidence to refute the
compelling data supporting a primary mechanical function for the complex. Moreover, such data
fail to provide compelling support that the dystrophin-glycoprotein complex actively regulates
cellular signaling, or that altered signaling initiates the pathologies observed in dystrophin-
deficient muscle. While these hypotheses certainly remain attractive (especially with respect to
development of treatments for muscular dystrophy), the current challenge to the field is to design
and perform experiments that rigorously test their validity.
In at least one respect, the dystrophin-glycoprotein complex as two-by-four analogy fails. When
a house becomes too small for its occupants, the two-by-fours supporting static walls are
demolished in order to expand rooms. In the case of muscle however, cells simultaneously grow
under the influence of muscle contraction so the “two-by-four” framework of muscle cells must
be sufficiently dynamic to expand with growth while simultaneously protecting against stress-
induced membrane damage. Several studies have demonstrated that the dystrophin-glycoprotein
complex and costameres are indeed dynamic structures capable of remodeling in vivo.21
However, a remaining challenge is to understand how such fascinating and opposing functions
are effected at the molecular level, or perhaps at the level of interacting protein networks.
Acknowledgements
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• Top▲
I thank Ariana Combs and Inna Rybakova for the blot images used in (Fig. 1) and Kevin
Sonnemann for helpful discussions. The author is supported by grants from the Muscular
Dystrophy Association and the National Institutes of Health (AR42423).
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Copyright © 2000-2011, Landes Bioscience and Springer Science+Business Media.
Contents

Table of Contents Page

• Adhesion Molecules
○ Paramyxovirus Entry
○ Biological Roles of Prion Domains
○ The Role of Neuropilin in Vascular and Tumor Biology
○ Structural and Functional Relation of Neuropilins
○ Neuropilin and Its Ligands in Normal Lung and Cancer
○ Neuropilin and Class 3 Semaphorins in Nervous System Regeneration
• Aging
○ Yeast RecQ Helicases: Clues to DNA Repair, Genome Stability and
Aging
○ Sensory Influence on Homeostasis and Lifespan: Molecules and Circuits
○ Post-Translational Modification of Cellular Proteins by Ubiquitin and
Ubiquitin-Like Molecules: Role in Cellular Senescence and Ageing
• Angiogenesis
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
 ○ Vascular Endothelial Growth Factor in Malignant Disease of the Central
Nervous System
○ Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-
Endothelial Cells: Autocrine Signalling by VEGF
○ Crosstalk Between VEGF and Bcl-2 in Tumor Progression and
Angiogenesis
• Apoptosis
○ Autophagy in Caenorhabditis elegans
○ Apoptosis Dependent and Independent Functions of Caspases
○ The Role of Caspases in Modulation of Cytokines and Other Molecules
in Apoptosis and Inflammation
○ Caspases, Bcl-2 Family Proteins and Other Components of the Death
Machinery: Their Role in the Regulation of the Immune Response
○ Learning from Deficiency: Gene Targeting of Caspases
○ Caspase Activation in Cancer Therapy
○ Caspase-Independent Cell Death Mechanisms
○ Caspases as Targets for Drug Development
○ In Situ Activation of Caspases Revealed by Affinity Labeling Their
Enzymatic Sites
• Atherosclerosis
○ Antigen Recognition by γδ T-Cells
• Autoimmunity
○ Targeting Antigen-Specific T Cells for Gene Therapy of Autoimmune
Disease
○ Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-
Induced Arthritis
○ Cytokines in the Treatment and Prevention of Autoimmune Responses
○ Involvement of Cytokines in the Pathogenesis of Systemic Lupus
Erythematosus
○ Gene Therapy-Based Approach for Immune Tolerance Induction Using
Recombinant Immunoglobulin Carriers
○ Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune
Thrombocytopenic Purpura
○ Gastroenterologic and Hepatic Diseases
○ Inflammatory Myopathies: Dermatomyositis, Polymyositis and Inclusion
Body Myositis
○ Immunogene Therapy with Nonviral Vectors
○ Cytokines and Chemokines in Autoimmune Disease: An Overview
○ CTLA-4 in Type 1 Diabetes Mellitus
 ○ 4-1BB as a Therapeutic Target for Human Disease
• Bioinformatics
○ Prediction of Protein Function Two Basic Concepts and One Practical
Recipe
• Biomaterials
○ Regulation of Medical Devices
○ Tissue Engineering Constructs and Commercialization
• Biosurfactants
○ Screening Concepts for the Isolation of Biosurfactant Producing
Microorganisms
• Biotechnology
○ Use of piggyBac and a Sindbis Virus for Foreign Gene Expression and
RNAi in the Silkworm
○ Molecular Properties of Voltage-Gated Calcium Channels
○ Why Government Is the Problem (and What to Do about It)
○ Transgenic Analysis of the Biological Functions of a Doublesex
Homologue in Bombyx mori
○ Carbon Nanostructures as a New High-Performance Platform for MR
Molecular Imaging
○ Foundations of E-Cell Simulation Environment Architecture
○ Electrophysiological Simulation of Developmental Changes in Action
Potentials of Cardiomyocytes
○ Distributed Cell Biology Simulations with the E-Cell System
○ Bacterial Vectors for RNAi Delivery
○ HSV as a Vector in Vaccine Development and Gene Therapy
• Cancer Development
○ Epithelial-Mesenchymal Transitions in Human Cancer
• Cancer Genetics
○ Cellular Functions of Menin
• Cancer Metastasis
○ Integrins in Cancer Cell Invasion
○ The Plasminogen Activation System in Cell Invasion
○ Maspin: Functional Insights from a Structural Perspective
○ Maspin and Pericellular Plasminogen Activation in Cell-Matrix
Interaction
○ Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating
Integrin Expression and Function
○ The Role of Maspin in Tumor Progression and Normal Development
 ○ The Role of Maspin in Human Placental Development
○ Keratinocyte Interactions with Fibronectin during Wound Healing
• Cell Biology
○ Intracellular Membrane Fusion
○ The Golgi Apparatus
○ Clathrin-Mediated Endocytosis
○ Decoding the Signaling Mechanism of Toll-Like Receptor 4 Pathways in
Wild Type and Knockouts
○ Carrier Motility
○ The Exocytic Pathway and Development
○ Memory Th1/Th2 Cell Generation Controlled by Schnurri-2
○ The “O” Class: Crafting Clinical Care with FoxO Transcription Factors
○ FOXP Genes, Neural Development, Speech and Language Disorders
○ Regulation and Coordination of Intracellular Trafficking: An Overview
○ Overview of Intracellular Compartments and Trafficking Pathways
○ Sumoylation as a Signal for Polyubiquitylation and Proteasomal
Degradation
○ Studies on the Very Large G Protein–Coupled Receptor From Initial
Discovery to Determining Its Role in Sensorineural Deafness in Higher
Animals
○ Autosomal Lyonization of Replication Domains During Early Mammalian
Development
○ X Chromosome Inactivation and Embryonic Stem Cells
○ NOTCH SIGNALING AND THE DEVELOPING HAIR FOLLICLE
○ NOTCH SIGNALING AND THE GENERATION OF CELL DIVERSITY IN
DROSOPHILA NEUROBLAST LINEAGES
○ THE NEURAL BASIS OF SEMANTIC AND EPISODIC FORMS OF SELF-
KNOWLEDGE: Insights from Functional Neuroimaging
• Cell Cycle
○ The Restriction Point of the Cell Cycle
○ DNA Damage-Independent Checkpoints from Yeast to Man
○ The Regulation of p53 Growth Suppression
○ Functional Interactions Between BRCA1 and the Cell Cycle
○ The Evolution of CDK-Activating Kinases
○ CDK-Activating Kinases in Higher Plants
○ Activating Phosphorylation of Cyclin-Dependent Kinases in Budding
Yeast
• Cell Invasion
○ Matrix Metalloproteinases in Cancer Cell Invasion
• Cell Metabolism
○ Theory of Organelle Biogenesis: A Historical Perspective
○ Microfibril-Associated Glycoprotein-1 (MAGP-1) and Other Non-fibrillin
Macromolecules Which May Possess a Functional Association with the
10 nm Microfibrils
○ Synaptic Endosomes
○ Endocytosis of Receptor Tyrosine Kinases: Implications for Signal
Transduction by Growth Factors
○ Macroautophagy in Mammalian Cells
○ Plant Lipocalins
○ The Plasma Lipocalins α1-Acid Glycoprotein, Apolipoprotein D,
Apolipoprotein M and Complement Protein C8γ
○ Molecular Biology of the OXPHOS System
○ Bacterial Lipocalins: Origin, Structure, and Function
○ Chaperone-Mediated Autophagy
○ Regulation of Paracellular Transport across Tight Junctions by the Actin
Cytoskeleton
○ Entry into the Endoplasmic Reticulum: Protein Translocation, Folding
and Quality Control
○ Tight Junction Proteins and Cancer
○ Membrane Resealing Mediated by Lysosomal Exocytosis
○ Transcriptional Regulation of Keratin Gene Expression
○ Lysosomal Proteases: Revival of the Sleeping Beauty
○ Preprotein Translocation through the Sec Translocon in Bacteria
○ Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a
RELevant Role in Cancer
○ Nuclear Import of Agrobacterium T-DNA
○ Keratins As Targets in and Modulators of Liver Diseases
○ Retinol Binding Protein and Its Interaction with Transthyretin
○ Keratin Intermediate Filaments and Diseases of the Skin
○ Important Mammalian Respiratory Allergens Are Lipocalins
○ Lipocalin Receptors: Into the Spotlight
○ α1-Microglobulin
○ Lipocalins in Clinical Medicine
○ Lysosomal Storage Disorders
○ Lipocalins in Arthropoda: Diversification and Functional Explorations
○ Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Glycodelin: A Lipocalin with Diverse Glycoform-Dependent Actions
○ Nonsecretory, Regulated Exocytosis: A Multifarious Mechanism
Employed by Cells to Carry Out a Variety of Functions
○ Protein Misassembly: Macromolecular Crowding and Molecular
Chaperones
○ Molecular Interaction Network of the Hsp90 Chaperone System
○ The Synapsins and the Control of Neuroexocytosis
○ Hsp90 and Developmental Networks
○ A Common Binding Site for Actin-Binding Proteins on the Actin Surface
○ The Role of Synaptotagmin and Synaptotagmin-Like Protein (Slp) in
Regulated Exocytosis
○ Cell-Free Synthesis of Defined Protein Conjugates by Site-directed
Cotranslational Labeling
○ Reverse Engineering Models of Cell Cycle Regulation
○ Nuclear Import of Plant Proteins
○ Dynamic Connections of Nuclear Envelope Proteins to Chromatin and
the Nuclear Matrix
○ Nuclear Envelope Dynamics in Drosophila Pronuclear Formation and in
Embryos
○ Nuclear Envelope Breakdown and Reassembly in C. elegans:
Evolutionary Aspects of Lamina Structure and Function
○ Laminopathies: One Gene, Two Proteins, Five Diseases..
○ Dynamics of Nuclear Envelope Proteins During the Cell Cycle in
Mammalian Cells
○ Calnexin and Calreticulin, Molecular Chaperones of the Endoplasmic
Reticulum
○ Calreticulin-Mediated Nuclear Protein Export
○ Calreticulin and the Endoplasmic Reticulum in Plant Cell Biology
○ Calnexin and Calreticulin, ER Associated Modulators of Calcium
Transport in the ER
○ ER Calcium and ER Chaperones: New Players in Apoptosis?
○ Calreticulin in Cytotoxic Lymphocyte-Mediated Cytotoxicity
○ A Role for Calreticulin in the Clearance of Apoptotic Cells and in the
Innate Immune System
 ○ Calreticulin and Tumor Suppression
○ Cell Surface Calreticulin: Role in Signaling Thrombospondin Anti-
Adhesive Activity
○ Calreticulin Regulation of Lung Endothelial NOS Activity
• Channels and Transporters
○ Cell-Cell Fusion: Transient Channels Leading to Plasma Membrane
Merger
○ Anion Conduction by CFTR: Mechanisms and Models
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Voltage-Dependent Inactivation of Voltage Gated Calcium Channels
○ A Brief History of Calcium Channel Discovery
○ Block of Voltage-Gated Calcium Channels by Peptide Toxins
○ Calcium Channel Block and Inactivation: Insights from Structure-
Activity Studies
○ Ca2+ Chemistry, Storage and Transport in Biologic Systems: An
Overview
○ Hepatic Copper Transport
○ Drug-Induced Cholestatic Liver Disease
○ Cell-Cell Channels and Their Implications for Cell Theory
○ Cytoplasmic Bridges in Volvox and Its Relatives
○ Gap Junctions: Cell-Cell Channels in Animals
○ The Tetrahymena Conjugation Junction
○ Mating Cell-Cell Channels in Conjugating Bacteria
○ Fusome as a Cell-Cell Communication Channel of Drosophila Ovarian
Cyst
○ Channels across Endothelial Cells
○ Cytonemes as Cell-Cell Channels in Human Blood Cells
○ Vegetative Hyphal Fusion in Filamentous Fungi
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Fat Absorption and Lipid Metabolism in Cholestasis
○ Genetics, Mutations, and Polymorphisms
○ Hepatocyte Transplantation and Liver-Directed Gene Therapy
○ Phylogeny of Major Intrinsic Proteins
• Chaperones
○ Nucleotide Exchange Factors for Hsp70 Molecular Chaperones
○ Functions of the Hsp90-Binding FKBP Immunophilins
• Circadian Rhythms
○ Circadian Organization in the Algal Flagellate Euglena
• Coagulation
○ Regulation of Tissue Factor Expression
○ Factor XI, TAFI and DIC
○ Cytokines as Regulators of Coagulation
○ DIC at the Intersection of the Thrombotic, Fibrinolytic and Inflammatory
Axes
○ Genetic Risk Factors for Disseminated Intravascular Coagulation
○ Endothelial Cell Perturbation and Disseminated Intravascular
Coagulation
○ Blood-Borne Tissue Factor (Including Microparticles)
• Cytokines/Growth Factors
○ IL-10 Gene Polymorphisms in Transplantation
○ The Structure of the Type 1 Insulin-Like Growth Factor Receptor
○ Interleukin-10 Gene Polymorphisms and Cancer
○ The Role of IL-10 in Autoimmune Pathology
• Development
○ Embryonic Salivary Gland Branching Morphogenesis
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Integrins and Development: Integrins in Skeletal Cell Function and
Development
○ Membrane Lipid Rafts and Their Role in Axon Guidance
○ Epithelial-Mesenchymal Transformation in the Embryonic Heart
○ GSK3-Signal Regulation of Pattern Formation in Dictyostelium: Wnt-
Like Pathways During Non-Canonical Multicellular Development
○ Functional and Ecological Effects of Isoform Variation in Insect Flight
Muscle
○ Change of Epithelial Fate: Lessons from Gastrulation in Drosophila
○ Cadherin-Mediated Cell-Cell Adhesion and the Microtubule Network
○ TGFβ-dependent Epithelial-Mesenchymal Transition
○ Branching Morphogenesis of the Prostate
○ Expression and Function of Pitx2 in Chick Heart Looping
○ Neural Crest and the Development of the Enteric Nervous System
○ Matrix Metalloproteases and Epithelial-to-Mesenchymal Transition:
Implications for Carcinoma Metastasis
○ Whole Genome Approaches to Studying Drosophila Muscle
Development
○ Muscle Morphogenesis: The Process of Embryonic Myoblast Fusion
○ Development of the Larval Somatic Musculature
○ The Pathophysiological Role of Impaired Calcium Handling in Muscular
Dystrophy
○ X-Ray Diffraction of Indirect Flight Muscle from Drosophila in Vivo
○ The Sarcoglycans
○ The Role of Insulin-like Growth Factors in the Epithelial to Mesenchymal
Transition
○ Epithelium–Mesenchyme Transitions Are Crucial Morphogenetic Events
Occurring During Early Development
○ How Is the Branching of Animal Blood Vessels Implemented?
○ Integrins and Associated Proteins in Drosophila Development
○ Roles for Integrins and Associated Proteins in the Haematopoietic
System
○ Development of the Cardiac Musculature
○ Shh/Gli Signaling During Murine Lung Development
○ New Perspectives in Shh Signalling?
○ Role of shh and Gli Signalling in Oligodendroglial Development
○ Branching Morphogenesis in Vertebrate Neurons
○ Sonic Hedgehog Signaling in the Developing and Regenerating Fins of
Zebrafish
○ Role of Hedgehog and Gli Signalling in Telencephalic Development
○ Structure and Function of the Dystrophin-Glycoprotein Complex
○ Caveolin-3 and Limb-Girdle Muscular Dystrophy
○ Lamins and Emerin in Muscular Dystrophy: The Nuclear Envelope
Connection
○ Cranial Neural Crest and Development of the Head Skeleton
○ Mesoderm Formation in the Drosophila Embryo
○ Neural Crest Delamination and Migration: Integrating Regulations of
Cell Interactions, Locomotion, Survival and Fate
○ Insect Flight Muscle Chemomechanics
○ The Role of Integrins in Cell Migration
○ Neural Crest Cell Plasticity: Size Matters
○ Neural Crest Stem Cells
○ Integrins: An Overview of Structural and Functional Aspects
 ○ An Evolutionary Perspective on Eukaryotic Membrane Trafficking
○ Slits and Their Receptors
○ Origins and Evolution of Cotranslational Transport to the ER
○ Origins and Evolution of the Actin Cytoskeleton
○ Comparison of Muscle Development in Drosophila and Vertebrates
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
○ The Genetic Regulation of Pigment Cell Development
○ Origin and Evolution of Self-Consumption: Autophagy
○ The Contribution of the Neural Crest to the Vertebrate Body
○ Dorsoventral Patterning of the Brain: A Comparative Approach
○ VEGF and Endothelial Guidance in Angiogenic Sprouting
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ CtBP and Hematopoietic Transcriptional Regulators
○ A New Member of the CtBP/BARS Family from Plants: Angustifolia
○ Simulation of Human Erythrocyte Metabolism
○ A Model Library of Bacterial Chemotaxis on E-Cell System
○ CtBP3/BARS and Membrane Fission
○ Hsp70-Mediated Protein Refolding in E-Cell
○ VEGF Receptor Signalling in Vertebrate Development
○ Vascular and Nonvascular Roles of VEGF in Bone Development
○ Morphogenesis of Epithelial Appendages: Variations on Top of a
Common Theme and Implications in Regeneration
○ Wnt/Wingless Signaling in Drosophila
○ The Role of Wnt Signaling in Vertebrate Head Induction and the
Organizer-Gradient Model Dualism
○ The Wnt Gene Family and the Evolutionary Conservation of Wnt
Expression
○ Secreted Antagonists/Modulators of Wnt Signaling
○ Patterning the Vertebrate Neural Plate by Wnt Signaling
○ Wnt/Wg and Heart Development
○ Wnt Signaling and Cell Migration
○ Neural Crest Cells and the Community of Plan for Craniofacial
Development: Historical Debates and Current Perspectives
• DNA Surveillance and Repair
 ○ Roles of Poly(ADP-Ribose) Metabolism in the Regulation of Centrosome
Duplication and in the Maintenance of Neuronal Integrity
○ PARP and the Release of Apoptosis-Inducing Factor from Mitochondria
○ DNA Damage Signaling through Poly(ADP-Ribose)
○ Dynamic Interaction between PARP-1, PCNA and p21waf1/cip1
○ Parp and Epigenetic Regulation
○ Genome Degradation by DNAS1L3 Endonuclease: A Key PARP-1-
Regulated Event in Apoptosis
○ Biochemical Studies of Voltage-Gated Ca2+ Channels
○ Role of Poly-ADP-Ribosylation in Cancer Development
○ The Fanconi Anemia/BRCA Pathway: FANCD2 at the Crossroad between
Repair and Checkpoint Responses to DNA Damage
○ Fluorescence-Signaling Nucleic Acid-Based Sensors
○ Trichothiodystrophy: A Disorder Highlighting the Crosstalk between
DNA Repair and Transcription
○ Mobile Genetic Elements of Malaria Vectors and Other Mosquitoes
○ Orchestration of Telomeres and DNA Repair Factors in Mammalian
Cells: Implications for Cancer and Ageing
○ Mechanisms of DNA Damage and Repair in Alzheimer Disease
○ Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks
in Mammalian Cells
• DNA Vaccines
○ The Introduction of New DNA Vaccines into Developing Countries
• Drug Design
○ A Conceptual Framework
○ Modeling Structure-Activity Relationships
○ Prediction of Drug-Like Properties
○ Evolutionary De Novo Design
○ Analysis of Chemical Space
• Endocrinology
○ Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated
Vesicle Exocytosis
○ Subcellular Compartmentalization of Insulin Signaling Processes and
GLUT4 Trafficking Events
○ Insulin Action in the Islet β-Cell
○ What Is Osteoporosis?
○ Insulin and IGF-I Receptor Structure and Binding Mechanism
 ○ Insulin Resistance
○ Insulin Action Gene Regulation
• Evolution
○ Ribozyme-Catalyzed Genetics
○ Origin and Evolution of DNA and DNA Replication Machineries
○ Life in a Tenuous Universe
○ The Frame for New Hypotheses of Evolution
○ Genomism and the Nature Trail
○ The Origin of Complexity
○ Our Young Planet: One Is Not a Choice
○ The Condensation of Life
○ The Origins of Species
○ Development of Biological Potential
○ Thoughts on Multi-Cellularity: How Nature Got Around Darwin
○ Natura non facit saltum (Nature does nothing in jumps)
○ The Invariance Concept
○ On the Evolution of Humans
○ Molecular Geneology
○ Experiments in Evolution
○ Quintessence
○ The Scope of Selection
• Extracellular Matrix
○ The Biogenesis and Cell Biology of Peroxisomes in Human Health and
Disease
○ Assembly of Microfibrils
• Gastroenterology
○ Nerve Regulation of Cholangiocyte Functions
○ Functional Heterogeneity of the Intrahepatic Biliary Epithelium
○ Bile Acid Interactions with Cholangiocytes
○ Estrogen Regulation of Cholangiocyte Proliferation
○ Nerve Regulation of Cholangiocyte Functions
○ Vascularization of the Intrahepatic Biliary Tree and Its Role in the
Regulation of Cholangiocyte Growth
○ Cytokine Regulation of Cholangiocyte Growth
○ Hyperemesis Gravidarum and Maternal Liver Disease
○ The Liver in Normal Pregnancy
 ○ Spectrum of Maternal Liver Disease
• Gene Expression
○ Stochastic Gene Expression: Dominance, Thresholds and Boundaries
○ Biological Consequences of Dosage Dependent Gene Regulation in
Multicellular Eukaryotes
○ GAGA: Structural Basis for Single Cys2His2 Zinc Finger-DNA Interaction
○ Identification of Mammalian E2F Regulatory Networks Using DNA
Microarray Hybridization Analyses
○ Homing Endonuclease I-TevI: An Atypical Zinc Finger with a Novel
Function
○ A Novel Test Statistic for the Identification of Local Selective Sweeps
Based on Microsatellite Gene Diversity
○ Periodic Selection and Ecological Diversity in Bacteria
○ LIM Domain and Its Binding to Target Proteins
○ MDM2: RING Finger Protein and Regulator of p53
○ Inferring Evolutionary History through Inter- and Intraspecific DNA
Sequence Comparison: The Drosophila janus and ocnus Genes
○ Selective Sweep in the Evolution of a New Sperm-Specific Gene in
Drosophila
○ The Superfamily of SCAN Domain Containing Zinc Finger Transcription
Factors
○ Putative Roles of kin17, a Mammalian Protein Binding Curved DNA, in
Transcription
○ CtBP Family Proteins: Unique Transcriptional Regulators in the Nucleus
with Diverse Cytosolic Functions
○ A Zinc Ribbon Motif Is Essential for the Formation of Functional
Tetrameric Protein Kinase CK2
○ Rapid Evolution of Sex-related Genes: Sexual Conflict or Sex-specific
Adaptations?
○ Repression of Transcription by Curved DNA and Nucleoid Protein H-NS:
A Mode of Bacterial Gene Regulation
○ Curved DNA and Transcription in Eukaryotes
○ PNA and Oligonucleotide Inhibitors of Human Telomerase
○ Possible Roles of DNA Supercoiling in Transcription
○ MDM2: RING Finger Protein and Regulator of p53
○ Gene Regulatory Networks
○ Do DNA Triple Helices or Quadruplexes Have a Role in Transcription?
○ The Biology of Telomeres in Hypotrichous Ciliates
○ Scaling Laws in the Functional Content of Genomes: Fundamental
Constants of Evolution?
○ Regulation of Cardiomyocyte Proliferation and Apoptosis
○ Cell Cycle Reactivation in Skeletal Muscle and Other Terminally
Differentiated Cells
○ The Role of Unusual DNA Structures in Chromatin Organization for
Transcription
○ Molecular Mechanisms of Male Sex Determination: The Enigma of SRY
○ DNA: Alternative Conformations and Biology
○ Curved DNA and Prokaryotic Promoters: A Mechanism for Activation of
Transcription
○ Scale-Free Evolution: From Proteins to Organisms
○ Bioinformatics: Mystery, Astrology or Service Technology?
○ Extracting Information for Meaningful Function Inference Through Text-
Mining
○ Microarrays and Gene Regulation Networks in Yeast
○ Transcriptional Repression by the CtBP Corepressor in Drosophila
○ Structural Determinants of CtBP Function
○ Analytical Evolutionary Model for Protein Fold Occurrence in Genomes,
Accounting for the Effects of Gene Duplication, Deletion, Acquisition
and Selective Pressure
○ Power Law Correlations in DNA Sequences
○ Transcriptional Networks in Mammalian Gene Regulation
○ DNA Primer Extension by Telomerase
○ Transcriptional Profiling of the Hepatic Growth Response
○ Expression of Hox Genes in the Nervous System of Vertebrates
○ Telomeres: Guardians of Genomic Integrity or Double Agents of
Evolution?
○ Alternative Lengthening of Telomeres in Mammalian Cells
○ Evolution of Telomere Binding Proteins
○ Drosophila Telomeres: A Variation on the Telomerase Theme
○ Telomerase Activity as a Marker of Tumor Cell Survival to Evaluate
Sensitivity of Neoplastic Cells to Cancer Treatment
○ Myotonic Dystrophy: Discussion of Molecular Basis
○ Roles for TERT and Telomerase in Cell Differentiation and Apoptosis
○ Molecular Mechanisms of TRS Instability
○ Yeast Telomerases: Structure, Mechanisms and Regulation
 ○ The Significance of Quantitative Evaluation of Telomerase Activity and
hTERT mRNA Expression in Colorectal Cancers
○ Human, Mouse and Yeast Telomerase
○ Telomerase in Mesothelioma: Diagnostic and Therapeutic Applications
○ Telomerase Activity in Neuroblastomas: A New Molecular Marker for
Treatment Stratification and Prognostic Grouping
○ Telomerase and Radiosensitivity of Human Tumors
• Heart
○ Origin of Mechanotransduction: Stretch-Activated Ion Channels
○ Regional Differences and Variability in Left Ventricular Wall Motion
• Heat Shock Proteins
○ Assembly of Protein Aggregates in Neurodegeneration: Mechanisms
Linking the Ubiquitin/Proteasome Pathway and Chaperones
○ The Role of Heat Shock Proteins during Neurodegeneration in
Alzheimer's, Parkinson's and Huntington's Disease
• Hematology
○ Other Proteins and Their Interactions with FA Gene Products
○ The Genetic Basis of Fanconi Anemia
○ The FANCC Gene and Its Products
• Immunology
○ Animal Models of OXPHOS Disorders
○ Molecular Recognition of Haptens by T Cells: More Than One Way to
Tickle the Receptor
○ Phospholipases and Phagocytosis
○ IgA and Mucosal Homeostasis
○ Carbohydrate-Based Targets and Vehicles for Cancer and Infectious
Diseases Vaccines
○ Small GTP Binding Proteins and the Control of Phagocytic Uptake
○ Calcium Signaling During Phagocytosis
○ Regulation of Phagocytosis by FcγRIIb and Phosphatases
○ Adding Complexity to Phagocytic Signaling: Phagocytosis-Associated
Cell Responses and Phagocytic Efficiency
○ V(D)J Recombination: Of Mice and Sharks
○ Opioid Receptors on Peripheral Sensory Neurons
○ Morphological Correlates of Immune-Mediated Peripheral Opioid
Analgesia
○ Functional Evidence of Pain Control by the Immune System
 ○ Opioid Receptor Expression and Intracellular Signaling by Cells
Involved in Host Defense and Immunity
○ Experimental Evidence for Immunomodulatory Effects of Opioids
○ The Immune-Suppressive Effects of Pain
○ Lipoxins as an Immune-Escape Mechanism
○ Dynamic Aspects of TCRα Gene Recombination: Qualitative and
Quantitative Assessments of the TCRα Chain Repertoire in Man and
Mouse
○ Viral TNF Inhibitors as Potential Therapeutics
○ CD8 T-Cell Memory Differentiation during Acute and Chronic Viral
Infections
○ Chromatin Mechanisms Regulating Gene Expression In Health And
Disease
○ Earthworm Immunity
○ TRIM PROTEINS AS RING FINGER E3 UBIQUITIN LIGASES
○ REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for
Treatment of Mast-Cell Related Diseases?
○ GASTROPOD IMMUNOBIOLOGY
○ MAST CELLS AND IMMUNOREGULATION/IMMUNOMODULATION
• Infectious Disease
○ Everything (or Almost Everything) You Want to Know about Genetically
Modified Mosquitoes for Malaria Control but Are (Maybe) Afraid to Ask
○ Predicting the Spread of a Transgene in African Malaria Vector
Populations: Current Knowledge and Limitations
○ Invasion and Intracellular Survival by Toxoplasma
○ Negative Signaling and Modulation of Macrophage Function in
Trypanosoma cruzi Infection
○ Pro-Inflammatory Responses in Macrophages during Toxoplasma
gondii Infection
○ Avoidance of Innate Immune Mechanisms by the Protozoan Parasite,
Leishmania spp
○ Insect Population Suppression Using Engineered Insects
○ Current and Emerging Approaches to Studying Invasion in
Apicomplexan Parasites
• Ischemia-Reperfusion
○ Therapeutic Utilities of SOD Mimetics: Cancer, Radiotherapy and SOD
Mimetics
○ Development of Manganic Porphyrin Mimetics of Superoxide Dismutase
Activity
 ○ Role of Superoxide in Post-Ischemic Liver Injury
○ Evaluation of a Superoxide Dismutase Mimetic As an Adjunct to
Interleukin 2 Based Cancer Therapy
• Medical
○ STATs and Infection
○ JAK/STAT Pathway Signalling in Drosophila Melanogaster
○ Disease Transmission Models for Public Health Decision-Making:
Designing Intervention Strategies for Schistosoma japonicum
○ Parameter Estimation and Site-Specific Calibration of Disease
Transmission Models
• Molecular Biology
○ RNA Modification Subsystems in the SEED Database
○ KIR Genes and Their Role in Spondyloarthropathies
○ Antibiotic Resistance in Bacteria Caused by Modified Nucleosides in
23S Ribosomal RNA
○ The “PACE” Concept Pointed at New Key Proteins Involved in RNA
Metabolism
○ DNA Demethylation
○ Adhesion-Dependent Modulation of Macrophage K+ Channels
○ Pseudouridine Formation, the Most Common Transglycosylation in RNA
○ Folate-Dependent Thymidylate-Forming Enzymes: Parallels between
DNA and RNA Metabolic Enzymes and Evolutionary Implications
○ The Interplay between RNA and DNA Modifications: Back to the RNA
World
○ Deciphering the Complex Enzymatic Pathway for Biosynthesis of
Wyosine Derivatives in Anticodon of tRNAPhe
○ Nucleic Acids Are Not Boring Long Polymers of Only Four Types of
Nucleotides: A Guided Tour
○ Chemokine Binding Proteins Encoded by Pathogens
○ Boomerangs, Bananas and Blimps: Structure and Function of F-BAR
Domains in the Context of the BAR Domain Superfamily
○ Gas7
○ Enzyme-RNA Substrate Recognition in RNA-Modifying Enzymes
• Nanomedicine
○ STAT1 and STAT3 in Tumorigenesis: Two Sides of the Same Coin?
• Neurodegenerative Disease
○ DSD-1-Proteoglycan/Phosphacan and Receptor Protein Tyrosine
Phosphatase-Beta Isoforms During Development and Regeneration of
Neural Tissues
○ Interleukin-10 and Psoriasis
○ Idiopathic Parkinson's Disease: Staging an α-Synucleinopathy with a
Predictable Pathoanatomy
○ Chromosome 1 and Other Hotspots for Parkinson's Disease Genes
○ Fibroblast Growth Factors
○ Neuronal Survival and Cell Death Signaling Pathways
○ Paved with Good Intentions: The Link between Cell Cycle and Cell
Death in the Mammalian Central Nervous System
○ α-Synuclein Physiology and Membrane Binding
○ Na Channels and Ca2+ Channels of the Cell Membrane as Targets of
Neuroprotective Substances
○ Heat Shock Proteins and Neuroprotection
○ Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain
Ischemia Following Delayed Intravenous Administration of
Neurotrophins
○ Neuroprotective Strategies in Animal and in Vitro Models of Neuronal
Damage: Ischemia and Stroke
○ Vascular Endothelial Growth Factor
○ Cell Cycle and Chromosome Segregation Defects in Alzheimer's
Disease
○ Neuroprotective Activity of Metabotropic Glutamate Receptor Ligands
○ Excitatory Amino Acid Neurotoxicity
○ Dopamine and Parkinson's Disease
○ Neurotrophins
○ Overview Αβ Metabolism: From Alzheimer Research to Brain Aging
Control
○ β-Secretase: Progress and Open Questions
○ APP α-Secretase, a Novel Target for Alzheimer Drug Therapy
○ γ-Secretase and Presenilin
○ Functional Roles of APP Secretases
○ Proteolytic Degradation of Αβ by Neprilysin and Other Peptidases
○ Αβ Degradation by Endothelin-Converting Enzymes
○ Ab Metabolism in Cholesterol-Enriched Membrane Microdomains
○ Amyloid β-Protein in Low-Density Membrane Domains
○ Transport-Clearance Hypothesis for Alzheimer's Disease and Potential
Therapeutic Implications
○ Potential Role of Endogenous and Exogenous Ab Binding Molecules in
Ab Clearance and Metabolism
 ○ Modulating Amyloid β Levels by Immunotherapy: A Potential
Therapeutic Strategy for the Prevention and Treatment of Alzheimer's
Disease
• Neuropharmacology
○ Diurnal 5-HT Production and Melatonin Formation
○ Pineal Gland and Cancer—An Epigenetic Approach to the Control of
Malignancy: Evaluation of the Role of Melatonin
○ Cell Adhesion Molecules
○ Risks of Chronic Hypnotic Use
○ Sleep Hippocampal Theta Rhythm and Sensory Processing
○ Cannabinoid Receptors and Signal Transduction
○ Protein Kinase A
○ A Comparison of Visual Analog Scale and Categorical Ratings in
Assessing the Patient's Estimate of Sleep Quality
• Neuroscience
○ Role of Semaphorins during Axon Growth and Guidance
• Nucleus
○ Riboflavin and Methylenetetrahydrofolate Reductase
○ Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR)
and Overview of Mutations/Polymorphisms
○ Methylenetetrahydrofolate Reductase Polymorphisms:
Pharmacogenetic Effects
○ Assays for Methylenetetrahydrofolate Reductase Polymorphisms
• Oncogenes
○ p53's Dilemma in Transcription: Analysis by Microarrays
○ TP63, TP73: The Guardian's Elder Brothers
○ Modes of p53 Interactions with DNA in the Chromatin Context
• Oncology
○ Fever, Pyrogens and Cancer
○ Gene Expression Profiling in Malignant Lymphomas
○ Cytoreduction, Peritonectomy and Hyperthermic Antiblastic Peritoneal
Perfusion for the Treatment of Peritoneal Carcinomatosis
○ Hyperthermic Isolated Limb Perfusion
○ Intracavitary Hyperthermic Perfusion
○ Locoregional Hyperthermia
○ Transcription of rDNA in the Yeast Saccharomyces cerevisiae
○ Pre-Ribosomal RNA Processing in Multicellular Organisms
 ○ PDGF Pathways and Growth of Basal Cell and Squamous Cell
Carcinomas
○ Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A
Radiation
○ Influence of Tumor Microenvironment on Thermoresponse: Biologic and
Clinical Implications
○ Physical Background and Technical Realizations of Hyperthermia
○ Effects of Local and Whole Body Hyperthermia on Immunity
○ Thermo-Chemo-Radiotherapy Association: Biological Rationale,
Preliminary Observations on Its Use on Malignant Brain Tumors
○ Molecular Mechanisms of ErbB2-Mediated Breast Cancer
Chemoresistance
○ Future Perspectives of Interstitial and Perfusional Hyperthermia
○ Roles of Multidrug Resistance Genes in Breast Cancer Chemoresistance
○ Insulin-Like Growth Factors and Breast Cancer Therapy
○ Novel Approaches for Chemosensitization of Breast Cancer Cells: The
E1A Story
○ Whole Body Hyperthermia at 43.5-44°C: Dreams or Reality?
○ Overview of Resistance to Systemic Therapy in Patients with Breast
Cancer
○ Microarrays for Cancer Diagnosis and Classification
○ Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines:
Clinical Results
○ Cellular Interactions in Nasopharyngeal Carcinomas
• Protein
○ Structure, Function and Assembly of Flagellar Axial Proteins
○ Implications of 3D Domain Swapping for Protein Folding, Misfolding and
Function
○ From Artificial Antibodies to Nanosprings:The Biophysical Properties of
Repeat Proteins
○ The Budding Yeast PCH/F-BAR Proteins
○ Gas7
○ The Coronin Family of Proteins
○ Diversity of WD-repeat Proteins
○ A Brief History of the Coronin Family
○ Phylogenetic, Structural and Functional Relationships between WD-and
Kelch-Repeat Proteins
○ The Role of Mammalian Coronins in Development and Disease
 ○ Invertebrate Coronins
○ Evolutionary and Functional Diversity of Coronin Proteins
○ Coronin: The Double-Edged Sword of Actin Dynamics
○ Coronin 1 in Innate Immunity
○ Molecular Phylogeny and Evolution of the Coronin Gene Family
○ Coronin Structure and Implications
○ Nuclear APC
○ Role of Mammalian Coronin 7 in the Biosynthetic Pathway
○ Post-Targeting Functions of Signal Peptides
• Reproductive Biology
○ Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor
Functions during Epidermal Development and Disease
○ Bi-Directional Cell Trafficking During Pregnancy: Long-term
Consequences for Human Health
○ Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular
Immunity
○ The Role of Corticotropin-Releasing Hormone (CRH) on Implantation
and Immunotolerance of the Fetus
○ Characterization of Human Dendritic Cells at the Maternal-Fetal
Interphase
○ Important Role of Shh Controlling Gli3 Functions During the Dorsal-
Ventral Patterning of the Telencephalon
○ Spatial and Temporal Regulation of Hair Follicle Progenitors by
Hedgehog Signalling
○ MHC Molecules of the Preimplantation Embryo and Trophoblast
○ The Role of Regulatory T Cells in Materno-Fetal Tolerance
○ Cytogenetics of Human Sperm
○ Preimplantation Genetic Diagnosis (PGD): Screening for Aneuploidy in
Human Oocytes and Polar Bodies
○ Proteases and Their Cognate Inhibitors of the Serine and
Metalloprotease Subclasses, in Testicular Physiology
○ Antioxidant Systems and Oxidative Stress in the Testes
• RNA
○ Protein-Switched Ribozymes
○ Proteins Carrying One or More Unnatural Amino Acids
○ Therapies of Nonsense-Associated Diseases
○ All Termination Events Are Not Equal: Premature Termination in Yeast
Is Aberrant and Triggers NMD
○ Role of SMG-1-mediated Phosphorylation of Upf1 in NMD
○ NMD in Drosophila: A Snapshot into the Evolution of a Conserved
mRNA Surveillance Pathway
○ The snoRNPs and Related Machines: Ancient Devices That Mediate
Maturation of rRNA and Other RNAs
○ Trytophanyl-tRNA Synthetases
○ Tyrosyl-tRNA Synthetases
○ Cytokines, Chemokines and Their Receptors
○ Valyl-tRNA Synthetases
○ Protein-Induced RNA Switches in Nature
○ Class I Lysyl-tRNA Synthetases
○ Glutaminyl-tRNA Synthetases
○ Asparaginyl-tRNA Synthetases
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
○ Aminoacyl-tRNA Synthetases and Disease
○ Human Upf Proteins in NMD
○ Phenylalanyl-tRNA Synthetases
○ Regulation of Gene Expression by Coupling of Alternative Splicing and
NMD
○ NMD and Human Disease
○ Polyadenylation and Degradation of RNA in Prokaryotes
○ Regulation of the Expression of Aminoacyl-tRNA Synthetases and
Translation Factors
○ Conformational Dynamics within the Ribosome
○ Tests of a Stereochemical Genetic Code
○ Evasion of Phagosome Lysosome Fusion and Establishment of a
Replicative Organelle by the Intracellular Pathogen Legionella
pneumophila
○ The End in Sight: Poly(A), Translation and mRNA Stability in Eukaryotes
○ Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized
for Gene Expression
○ Mechanism of Translation Initiation in Eukaryotes
○ A Prelude to Translational (Re)Initiation
○ Protein Tagging and Ribosome Rescue in Bacteria Requires the
Recognition of Transfer-Messenger RNA by an Aminoacyl-tRNA
Synthetase
 ○ Mitochondrial Aminoacyl-tRNA Synthetases
○ Transfer RNA Structure and Identity
○ Post-Transcriptional Gene Silencing in Plants
○ Turnover of Mature miRNAs and siRNAs in Plants and Algae
○ miRNAs need a Trim Regulation of miRNA Activity by Trim-NHL Proteins
○ Structural Components and Architectures of RNA Exosomes
○ C. ELEGANS STAR PROTEINS, GLD-1 AND ASD-2, REGULATE SPECIFIC
RNA TARGETS TO CONTROL DEVELOPMENT
• Signal Transduction
○ Genetic Susceptibility to Infectious Diseases Linked to NRAMP1 Gene in
Farm Animals
○ FasL-Independent Activation of Fas
○ Plant Metal Transporters with Homology to Proteins of the NRAMP
Family
○ Regulation of Bacterial MntH Genes
○ Physiological Roles and Mechanisms of Signaling by TRAF2 and TRAF5
○ Metal-ion Transporters— From Yeast to Human Diseases
○ The Function of Toll-Like Receptors
○ Regulation of the RhoGTPases by RhoGDI
○ How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-
GLI Signaling as Anti-Cancer Therapy?
○ Rho Family GTPases and Cellular Transformation
○ GLI Genes and Their Targets in Epidermal Development and Disease
○ Regulation of Cell Motility by Abl Family Kinases
○ The Patched Receptor: Switching On/Off the Hedgehog Signaling
Pathway
○ Shh Expression in Pulmonary Injury and Disease
○ Regulation of Cell Adhesion Responses by Abl Family Kinases
○ Abl Family Kinases in Mammalian Development
○ Abl and Cell Death
○ Mechanisms of Activation of Abl Family Kinases
○ Regulation of Cytoskeletal Dynamics and Cell Morphogenesis by Abl
Family Kinases
○ TRAFs in RANK Signaling
○ Abelson Family Protein Tyrosine Kinases and the Formation of Neuronal
Connectivity
○ The LTβR Signaling Pathway
 ○ Neurons, Neurotrophins and Ceramide Signaling: Do Domains and
Pores Contribute to the Dichotomy?
○ The Role of Serine/Threonine Protein Phosphatases in Ceramide
Signaling
○ Chaperone Effects on Prion and Nonprion Aggregates
○ Insights into the Modulation of Ceramide Metabolism by Naturally
Occurring and Synthetic Sphingolipid Analogs as Monitored by
Electrospray Tandem Mass Spectrometry
○ Ceramide Glycosylation and Chemotherapy Resistance
○ S-Modulin
○ Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by
Divalent Cations and Polyamines
○ Target Recognition of Guanylate Cyclase by Guanylate Cyclase-
Activating Proteins
○ Centrins, a Novel Group of Ca2+-Binding Proteins in Vertebrate
Photoreceptor Cells
○ The TRP Calcium Channel and Retinal Degeneration
○ Ca2+-dependent Control of Rhodopsin Phosphorylation: Recoverin and
Rhodopsin Kinase
○ The Complex of cGMP-gated Channel and Na/Ca2+, K Exchanger in Rod
Photoreceptors
○ RGS9-1 Phosphorylation and Ca2+
○ Ceramide in the Regulation of Neuronal Development: Two Faces of a
Lipid
○ Therapeutic Implications of Ceramide-Regulated Signaling Cascades
○ Photoreceptor Degeneration and Ca2+ Influx through Light-Activated
Channels of Drosophila
○ Regulation of the Rod Photoreceptor Cyclic Nucleotide-Gated Channel
○ Mouse Models to Study GCAP Functions in Intact Photoreceptors
○ Using Mutant Mice to Study the Role of Voltage-Gated Calcium
Channels in the Retina
○ Calcium Channels at the Photoreceptor Synapse
○ Biosynthesis of Sphingolipids in Plants (and Some of Their Functions)
○ Ceramide 1-Phosphate in Cell Survival and Inflammatory Signaling
• Stem Cells
○ Knockout Mouse Models of Cytokine Action in Hematopoietic Stem Cell
Regulation
○ Cytokines, Receptors and Signalling Pathways Involved in Macrophage
and Dendritic Cell Development
• Tissue Engineering
○ Scleroderma Lung Fibroblasts: Contractility and Connective Tissue
Growth Factor
○ Repair of Osteochondral Lesions
○ Regulatory Issues: Down to the Bare Bones
○ Anatomy and Physiology of the Spinal Cord
○ Encouraging Regeneration of Host Neurones: The Use of Peripheral
Nerve Bridges, Glial Cells or Biomaterials
○ Replacement of Specific Neuronal Populations in the Spinal Cord
○ Replacement of Specific Populations of Cells: Glial Cell Transplantation
into the Spinal Cord
○ In Vitro Endothelialization: Its Contribution Towards an Ideal Vascular
Replacement
○ Biocompatibility of Polyurethanes
○ Tissue Repair in Asthma: The Origin of Airway Subepithelial Fibroblasts
and Myofibroblasts
○ Functional Assessment of Fibroblast Heterogeneity by the Cell-Surface
Glycoprotein Thy-1
○ Pro-Invasive Molecular Cross-Signaling between Cancer Cells and
Myofibroblasts
○ Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinase and
Matrix Turnover and the Fate of Hepatic Stellate Cells
• Transplant
○ Polyomavirus Allograft Nephropathy: Clinico-Pathological Correlations
○ Metabolic Management
• Vaccines
○ Immune Responses to DNA Vaccines: Induction of CD8 T Cells
○ Neisseria meningitidis Vaccines
○ DNA Vaccines against Bacterial Pathogens
○ Dendritic Cells: Important Adjuvants During DNA Vaccination
• Viruses
○ A Role for Chemokine Activity in Alphavirus Pathogenesis: Evidence
from the Analysis of Polyarthritis and Myalgia Post-Ross River Virus
Infection
○ Evolutionary Aspects of Human Endogenous Retroviral Sequences
(HERVs) and Disease
○ Structure and Replication of Hepatitis Delta Virus RNA
○ Hepatitis Delta Virus RNA Editing
 ○ Hepatitis Delta Antigen and RNA Polymerase II
○ Transforming Activities of JC Virus Early Proteins
○ DNA Packaging by Bacteriophage P22
○ Regulation of T Cell Immunity by OX40 and OX40L
○ BK Virus, JC Virus and Simian Virus 40 Infection in Humans, and
Association with Human Tumors
○ The ø29 DNA Packaging Motor: Seeking the Mechanism
○ Phylogenomics and Molecular Evolution of Polyomaviruses
○ Urine Cytology Findings of Polyomavirus Infections
○ Immunity and Autoimmunity Induced by Polyomaviruses: Clinical,
Experimental and Theoretical Aspects
○ Soluble Chemokine Binding Proteins Encoded by Viruses
○ Bacteriophage Lambda Terminase and the Mechanism of Viral DNA
Packaging
○ DNA Packaging in Bacteriophage T4
○ Bacteriophage SPP1 DNA Packaging
○ Polyomavirus-associated Nephropathy in Renal Transplantation: Critical
Issues of Screening and Management
○ Entry of Herpesviruses into Cells: The Enigma Variations
< PrevNext >

Go to:

• Top▲
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References
Madame Curie Bioscience Database [Internet].

Austin (TX): Landes Bioscience; 2000-.

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• Introduction
• Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex
• In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex
• Expanding beyond the Dystrophin-Glycoprotein Complex
• An Engineering Design Analogy
• References

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• Mycology Questions 2007: Feedback
• 1) Dark hyphae are one reason for a fungal isolate having a dark
appearance macroscopically (e.g with the phaeohyphomycetes), but
sometimes hyalohyphomycetes have a dark thallus even though their hyphae
is colourless. Explain.
• A
•
• key
•
• feature
•
• in
•
• the
•
• early
•
• differentiation
•
• and
•
• identification
•
• of
•
• fungi
•
• is
•
• determining
•
• which
•
• ones
•
• have
•
• pigmented
•
• hyphae.
•
• The
•
• fungi
•
• that
•
• have
•
• pigmented
•
• hyphae
•
• usually
•
• have
•
• a
•
• dark
•
• colony,
•
• but
•
• not
•
• always.
•
• On
•
• the
•
• other
•
• hand,
•
• plenty
•
• of
•
• fungi
•
• have
•
• dark
•
• colonies,
•
• especially
•
• dark
•
• green
•
• even
•
• though
•
• their
•
• hyphae
•
• are
•
• hyaline
•
• and
•
• colourless.
•
• This
•
• is
•
• because
•
• pigmentation
•
• of
•
• conidia
•
• also
•
• contributes
•
• to
•
• the
•
• colour
•
• of
•
• the
•
• colony.
•
• Bear
•
• in
•
• mind
•
• that
•
• conidia
•
• pigmentation
•
• is
•
• of
•
• virtually
•
• no
•
• value
•
• in
•
• the
•
• identification
•
• of
•
• fungi.
•
• 2) Explain how dermatophyte test medium is useful in detecting and
identifying dermatophytes. How does the medium work? Are all fungi that
grow on the medium and produce a red colour definitely dermatophytes?
• DTM can be used in a number of ways in the detection and identification of
dermatophytes, and some of these are addressed in other questions and
answers within this set of questions. I won't cover all the ways in which it can
be used in my answer, but give you an example of a way in which it can
really be useful.
•
• Suppose you isolate a fungus from a specimen in which you might reasonably
expect to find a dermatophyte. If on microscopic examination of the culture,
sufficient conidia are present to produce an identification, there is no need to
then set up a DTM. But what if the microscopy is unrewarding? In that case,
why not set up a DTM at the same time as you set up the other media that
you hope will induce conidiation. Again, if these other media are able to
induce sufficient conidiation to produce a microscopic identification, then the
DTM (which should be positive by then if the isolate is a dermatophyte) will
be helpful but still not really necessary. But what if the initial second batch of
media still do not produce sufficient conidia to give an identification. At this
point, if the DTM was negative, then it would be reasonable to conclude that
the isolate was probably not a dermatophyte and cut your losses, but if the
DTM was positive, it would be worthwhile selecting some different media to
try and induce conidiation.
• To be useful, DTM must be selective and differential. Most students
mentioned that DTM contains antibacterial and antifungal (saprophytes)
agents, but not many mentioned the actual differential agent. Phytone is a
relatively complex polypeptide that most organisms are unable to digest.
Since dermatophytes have enzymes able to break down keratin, then these
same enzymes presumably also allow the dermatophytes to break down the
phytone polypeptide. The metabolic endproducts of polypeptide metabolism
are usually alkaline, and in this case produce a red colour with the pH
indicator.
•
• Although it is relatively uncommon it is possible for DTM to produce false
positives. This may be because a particular non dermatophyte fungal isolate
is resistant to cyclohexamide or is able to slowly overcome the inhibition, and
is also able to hydrolyse phytone, or, it may be because you have a fungus
that can overcome the inhibitory effect of the cyclohexamide and a small
amount of bacterial growth that might provide the pH change required to
produce a red colour. In this context it is possible for a dermatophyte to give
a false negative if bacterial contamination of the slope is able to undo the pH
change produced by the dermatophyte.
•
• Don't overdo this issue about bacterial contaminants producing false results.
You need to have a pretty unusual set of circumstances coinciding before it
will happen. First you must have bacterial contamination which is unlikely
from a subculture from a primary selective fungal plate and needs the
bacteria to be resistant to whatever antibacterial agent in the primary
medium and the DTM, and then you need the bacterial growth to sufficiently
change the pH to overide the change induced by bacterial growth.
•
• So, a red DTM is not definitely a dermatophyte. BUT SO WHAT. The result is
not used in isolation, but in combination with other results such as
microscopy of the isolate which would "suss" out any false positives.
•
• DTM is widely accepted as a sufficiently sensitive and specific medium for
initial differentiation of dermatophytes from non dermatophyte fungi.
•
• There has recently been some debate regarding the performance of the
original DTM medium, with concern about lack of specificity. A number of
studies have shown that a number of non dermatophyte fungi can overcome
the concentration of cyclohexamide and not only grow, but also produce a
red colour change similar to that produced by dermatophytes.
•
• Salkin et al (1997) have produced a new medium, dermatophyte
identification medium (DIM) that is reported as having superior specificity to
DTM without any loss of sensitivity. DIM has a slightly different substrate,
 uses bromcresol purple as a pH indicator and has a higher concentration of
cyclohexamide. The exact formulation was not published presumably
because of the intention to patent the medium and sell it commercially.
•
• The published results from Salkin et al are impressive. Of 223 dermatophytes
tested, only one did not produce a visible alkaline shift with the bromcresol
purple. The sensitivity was greater than 99%. However, 15 of 73 non
dermatophytes that were able to grow on the DIM were able to also cause an
alkaline pH shift. This initially gives a specificity of only around 95%, but
since all 15 problematic non dermatophytes were clearly dematiacious, they
are easily recognised as non dermatophytes on the basis of colonial
morphology. When the reaction on DIM is considered in conjunction with
colonial morphology, then the specificity approaches 100%.
•
• In both the media (DTM and DIM), I have only vaguely referred to the
substrate. In DTM, the substrate is phytone, and in DIM it is neopeptone).
Both these substrates are peptones; that is they are a heterogeneous mixture
of different size polypetides formed from the enzymic hydrolysis of proteins.
Phytone comes from soy protein, whereas neopeptone comes from animal
protein.
•
• So is there any reason why the different media use different peptone
sources? I don't know, but I suspect the change was more to do with making
DIM sufficiently different from DTM to make it possible to patent the new
medium. The same might be true of the change from phenol red to
bromcresol purple. Maybe the only real functional difference between the
media is the concentration of the cyclohexamide?
•
•
• 3) In some laboratories, the Sabs (or Sabs chlor) and the Mycobiotic are used
routinely on all specimens, but on specimens with a positive direct
microscopy, the DTM medium is included in the primary media - what is the
rationale behind this approach?
• So you have grown a fungus from a skin scraping! Is it a dermatophyte?
•
• The fastest way to find out is to examine the microscopic morphology, and
with a bit of luck it will be typical for a particular dermatophyte, and not only
will you be able to identify it as "a dermatophyte", you will also be able to
give it a specific name.
•
• But what if the isolate is not being cooperative and is not producing sufficient
conidia on which to make an identification? Quite often, all you get on initial
examination of a fresh isolate is "sterile hyphae". Subculturing onto other
 media to stimulate conidiation is an obvious next step, although it may take 2
to 3 weeks to have sufficient growth for microscopic examination.
•
• One way of dealing with this is to subculture the organism onto a DTM slope
and look for a colour change. The only problem being that this will take a
week or so to go positive.
•
• If you want to have a faster answer, why not include a DTM slope with the
primary media inoculated initially? This would give you an answer at the
same time as you saw growth on the mycobiotic agar. The problem with this
is that you probably only grow dermatophytes from about 5% of the
specimens that you culture. This means that for every 5 DTM slopes that are
useful, 95 are wasted. In a cost conscious environment, this may not be
acceptable. There would be less waste if it were possible to identify (prior to
culture) those samples that were more or less likely to contain a
dermatophyte. This is achieved by doing direct microscopy, and on those that
are positive (and therefore very likely to have a dermatophyte) you include a
DTM, and on those that are negative (less likely to have a dermatophyte) you
don't. As you know, a negative direct microscopy does not mean that you will
not grow a dermatophyte; but using this strategy of media use, you will need
to subculture a possible dermatophyte isolate onto DTM to find out.
•
• I wonder (well actually I don't wonder, but I'm wondering on your behalf) if
the specificity and sensitivity of DTM (or DIM) would be different when used
directly on clinical material as opposed to being used on subcultures from
primary plates? I think they would both be worse, and it is up to you to think
about why.
•
•
• 4) Would these organisms (Scopulariopsis and Fusarium)) be recovered if
nail specimens were only cultured on media containing cyclohexamide.
• No.
•
• Scopulariopsis brevicaulis
• and
• Acremonium
• spp. are in fact hyaline hyphomycetes, and classified taxonomically in the
same broad group of fungi as
• Penicillium
• spp. and
• Aspergillus
• spp. These are the kinds of "common contaminant" fungi for which
cyclohexamide is included as an inhibitory agent to make culture media
selective for dermatophytes. So, if you get "dermatophyte tunnel vision" and
 only culture specimens on media containing cyclohexamide, then there is a
risk that some non dermatophyte pathogens may be missed.
• Dermatophyte "tunnel vision" is how I refer to the common misconception
that all "tinea" like lesions are caused by dermatophytes. They are not, and
this applies especially to onychomycosis where non dermatophytes are well
recognized.
•
•
• 5) Are there any clinical features that might suggest either Scopulariopsis or
Acremonium as the causative agents of a particular case of onychomycosis?
• Nails infected with
• Scopulariopsis brevicaulis
• tend to develop a brown colouration and crumbly texture, whereas those
infected with
• Acremonium
• spp. tend to be whitish.
•
• Like all such clinical findings, they are useful hints, but not diagnostic.
•
• Would you be able to differentiate (sometimes, but not always) a nail infected
with
• Acremonium
• spp from a nail infected with
• Scopulariopsis brevicaulis
• or a nail infected with a dermatophyte? If your answer is NO, then you should
and revise the online tutorial.
•
• 6) Similarity to which other very common hyaline fungus (which is a common
contaminant of laboratory cultures) often leads to cultures of Scopulariopsis
being prematurely discarded as not significant? What are the major
distinguishing features?
• The conidiophore of
• Scopulariopsis
• is sometimes referred to as a "penicillus" which means "brush like".
• Isn't it a pity that the science (?art) of mycology seems obsessed with
seemingly obtuse terminology ! What is wrong with simply saying "brush
like"?
• Needless to say then, that there is some similarity between
• Scopulariopsis
• spp. and
• Penicillium
• spp. The most obvious microscopic difference being that the conidiophores
of
• Scopulariopsis
• are shorter, the conidia larger and usually spiny or rough.
•
• 7) What are the individual purposes of the chloramphenicol and
cyclohexamide?
• Chloramphenicol is a broad spectrum antibacterial agent, and cyclohexamide
is a broad spectrum antimycotic agent. They can be used to suppress the
growth of some bacterial/mycotic agents that may otherwise outgrow,
obscure and therefore prevent the detection in culture of certain fungi from
some clinical specimens.
• There is no choice of antifungal (anti saprophytic fungi) agent, as only
cyclohexamide inhibits the majority of saprophytes while NOT inhibiting the
dermatophytes, but there is a choice of antibacterial agent.
•
• Some laboratories, or some culture media recipes actually use a combination
of gentamicin and tetracycline. It doesn't really matter as long as the effect is
broad spectrum bacterial inhibition.
• 8) Which medium would be most suitable for culturing clinical specimens for
dermatophytes?
• Dermatophytes are commonly grown from specimens that are likely to
contain numerous other organisms: both of a bacterial and fungal nature.
They are also relatively slow growing, sometimes taking up to 4 weeks to
become visible on first isolation, so it is necessary to use selective media.
Since dermatophytes are known to be resistant to cyclohexamide, a culture
medium containing both an antibacterial agent (such as chloramphenicol or
gentamicin) and cyclohexamide would be most suitable.
•
• Even though the mycobiotic selective agar is considered the best for
culturing dermatophytes, you need to remember that in many cases fungi
other than dermatophytes (including fungi that are sensitive to
cyclohexamide) may be involved. Classic examples are
• Candida albicans
• from either skin or nails, or
• Scopulariopsis brevicaulis
• from nails.
•
• This issue is further explored in question 14.
•
• 9) Are any of the class subclinical carriers of dermatophytes and which
dermatophytes might you expect in this situation?
• In 2000, 2 isolates of
• T. mentagrophytes
• and 1 isolate of
• T. rubrum
• were isolated from students who were apparently asymptomatic.
•
• In 2001, one student was clearly symptomatic, and a dermatophyte was
isolated, and one other student that gave a positive culture was
asymptomatic.
•
• In 2002, one student grew a dermatophyte and he was actually symptomatic.
It turns out that he actually had two different dermatophytes which in my
experience is quite unusual. This year (2006), no students were carriers, but
one student was infected with E. flocossum. With asymptomatic
dermatophyte infection/carrier states in humans, you would most definitely
expect an anthropophilic organism. The organism must be well adapted to
the host so that only a very weak host immune response is elicited. In this
context it is important to stress the fact that the symptoms associated with
dermatophytosis are usually due to the host response and not to any
destructive enzymes or toxins that the fungus produces, nor to any invasion
of living tissue since the dermatophytes only infect the outer dermis.
•
• Trichophyton rubrum
• is known to be capable of causing an asymptomatic infection/carrier state on
the foot (in particular in the toe webbing) and this has been linked to the
evolutionary adaptation of this previously tropical fungus to colder climates.
•
•
• [Link]
• has more than one variety:
• T. mentagrophytes
• var
• mentagrophytes
• is zoophilic and tends to have a more typical microscopic morphology,
including spherical microconidia in dense clusters. This variety tends to be
involved in tinea corporis.
•
• T. mentagrophytes
• var
• interdigitale
• is anthropophilic and is more often involved in tinea pedis and
onychomycosis. The microconidia produced by this variety tend to be less
spherical and more pyriform in shape and therefore look more like typical
microconidia from a
• T. rubrum
• . If these strains produce spiral hyphae, then identification is easy, but if they
don't, then further tests may be required to differentiate them from
• T. rubrum.
•
• It seems likely that the isolates of
• T. mentagrophytes
• from students in the year 2000 were var interdigitale.
• There was also another student in 2000
• from which both
• E. floccosum
• and
• T. rubrum
• was isolated but this person was symptomatic.
•
• In 2001, the isolates from both students (symptomatic and asymptomatic
were not fully identified, but on initial microscopy tended to resemble
• T. rubrum.
•
• 10) What is the purpose of KOH in direct fungal microscopy? How do you
determine how long to digest for? Direct microscopy is always important
because it provides immediate information about the presence or absence of
fungi in the specimen, and in some situations it might also provide some
clues as to the identity of the organism.
•
• One of the problems with direct microscopy involving tissues infected with
fungi is the relative sparsity of fungal elements. The relative thickness of skin
scrapings and hair and nail clippings also makes it difficulty to see the
relatively inconspicuous fungal elements.
•
• Potassium hydroxide (usually a 10 to 15% solution) can be used to digest or
clear the specimen. The KOH effectively breaks down the keratinous tissue
whilst not significantly affecting the chitinous fungal cell wall. After sufficient
digestion, the sample can be squashed to make a thinner preparation for
microscopy.
•
• The time required for sufficient digestion depends on the nature and
thickness of the specimen. Fine pieces of skin might be sufficiently cleared
after 5 to 10 minutes, whereas thick pieces of skin may require a couple of
hours, and thick nail clipping may even require overnight digestion.
•
• Heating the KOH specimen mixture can speed up the digestion process as
can the addition of some dimethyl sulphoxide (DMSO) which helps the KOH
penetrate the specimen.
•
• One important precaution with digestion is not to over do it because although
the fungal elements are relatively inert to the digestion process they will
ultimately be destroyed which is why you cant use a digest for a permanent
slide.
•
• To help visualise the fungal elements after digestion they can be stained with
some blue or black ink. Lactophenol cotton blue tends to be decolourised by
the alkaline conditions and should not be used. The ink can be added after
digestion, or it can be added to the KOH to be used as a dual digestion/stain
reagent.
•
• Note that all these preparations (stained or unstained) are wet preparations,
in other words, you have the specimen and fluid (KOH etc) on a slide with a
coverslip.
•
• 11) How reliable is the direct microscopic examination of skin and nail
specimens in the diagnosis of dermatophytosis - which do you think is better,
the PPV or NPV?
• Direct examination of skin and nail specimens for the presence of "fungal
elements" is an established laboratory approach for the rapid diagnosis of
dermatophytosis. In general, this approach is quite specific in that there are
not many situations in which fungal elements seen on direct microscopy are
not due to the presence of a dermatophyte. Similarly, it is unlikely that non
fungal structures (ie artefacts) are misidentified as fungal elements. So a
positive test (detection of fungal elements) is usually associated with disease:
ie good PPV.
•
• On the other hand, due to sparsity of fungal growth in some
lesions/specimens and the relative frequency that small and indistinct fungal
elements are missed, direct microscopic examination is relatively insensitive.
So a negative test (fungal elements not detected on direct microscopy) does
not exclude dermatophytosis (or any other fungal infection): ie poor NPV.
•
• In general, direct microscopy on skin specimens is probably both more
sensitive and specific than similar tests on nail specimens. This is because
the quality of specimen is usually better with skin scrapings than nail
clippings, and the specimen is easier to clear with KOH, so that it is easier to
see the fungal elements and there is less "rubbish" that may be mistaken for
fungal elements.
•
• It should be noted that although dermatophytes are the most common cause
of fungal skin and nail infections, there are other causes. Most notably,
• Malassezia furfur
• and
• Candida albicans
• for skin, and
• Candida albicans
• ,
• Scopulariopsis brevicaulis
• ,
• Acremonium
• ,
• Aspergillus
• and
• Fusarium
• for nails. Although it may sometimes be possible to differentiate some of
these causes on the basis of the direct microscopy, it is frequently
impossible. In the absence of any other evidence, considering "fungal
elements" to most probably be dermatophytes until proven otherwise seems
a reasonable inference.
•
• 12) What are the advantages and disadvantages compared to culture?
• The advantages of direct microscopy are that a positive result is available in
a couple of hours as opposed to 2-3 weeks. This means that appropriate
therapy can be initiated sooner. This is particularly important in some cases
because one of the best drugs for treating dermatophytosis (Terbanifine) is
available (at normal cost as opposed to extra cost) only if there is supporting
evidence of infection from the laboratory. When you think about this
regulatory (and obviously cost saving) approach by the government, it must
mean that the extra cost of pathology tests (to establish the diagnosis) is less
than the cost of the extra drug that may otherwise be used on "non
dermatophyte" and possibly "non fungal"skin conditions.
•
• The disadvantage of direct microscopy is that it is much less sensitive than
culture, and even though direct microscopy is acceptably specific (ie few
false positives), it is still less specific than culture. In addition, a positive
direct microscopy simply tells you that an infection is caused by a
dermatophyte (most probably); it does not tell you which dermatophyte.
Now, even though the specific identity of the dermatophyte has no direct
bearing on the drug prescribed for treatment, the identity will have an impact
on how the patient is managed. For example, do the family pets need to
looked at or has the infection been acquired in some other way.
•
• It is worth looking at the special case of onychomycosis with respect to the
sensitivity of direct microscopy compared to culture. In some studies, up to
half of the infected nail clippings failed to grow on culture. In other words,
direct microscopy of nail specimens might be about equally sensitive as
culture. It is actually better to say "equally insensitive" as this reinforces the
fact that especially with nail specimens, it is important to do both direct
microscopy and culture.
•
• 13) What possible explanations are there for a positive direct microscopy
and a negative culture?
• When answering this question, there is an assumption that the specimen is
being analysed within the context of "skin, nail or hair sample being
examined for the presence of a dermatophyte". In this context, if you have a
positive direct microscopy and a negative culture there are 2 broad
explanations. Firstly, it may be a false positive microscopy and a true
negative culture; ie the patient does not have a dermatophyte infection.
Alternatively, the direct microscopy may be truly positive and the negative
culture a false negative; ie the patient does have a dermatophyte infection.
•
• Consider the possibilities for false positive microscopy. The fungal elements
observed may have been artefact, or alternatively the fungal elements may
have been non dermatophyte fungi that were present either as contaminants
or colonisers, or indeed in some cases as pathogens albeit "non
dermatophytes".
•
• There are more possibilities for a false negative culture.
•
• The patient may have been receiving some form of treatment that may
hinder the ability to culture the organism although the fungal elements in the
tissue would remain visible.
•
• It is also possible that the distribution of fungal elements is not consistent
through the specimen and it is not unusual for "the best piece" to be used for
microscopy and then the remainder for culture.
• It is important to stress that if you only receive a small amount of specimen,
it is probably best to use the majority (or even all) for culture since this is the
most sensitive and specific test
• . It is also possible that despite the use of selective media, the presence of
the dermatophyte in the culture is obscured by the overgrowth of bacterial
and fungal contaminants. It is also possible (unfortunately) although
hopefully not probable, that a dermatophyte is grown on culture but
discarded because the individual handling the analysis fails to recognise the
fungus as a dermatophyte.
•
• There are also a couple of other scenarios that do not fit neatly into the two
broad categories just discussed.
•
• There are occasions when there may be positive direct microscopy but a
"negative culture" that isn't really negative. For example some fungal
skin/nail infections can be caused by "non dermatophyte" fungi, especially
• Candida albicans,
• which can cause both skin rashes and onychomycosis. In this context, if you
only look for dermatophytes then there will be occasions when other fungi
that may be pathogenic will be overlooked simply because they are not
dermatophytes.
•
• 14) In what type of fungal infection of the skin is direct microscopy always
more sensitive than culture?
• In tinea versicolor (caused by
• Malassezia furfur
• ) the only reliable means of laboratory diagnosis is through direct
microscopy. This is because the organism is very difficult to grow and
certainly would not grow on the types of culture systems used for routine
culture of skin scrapings. Since the culture will always be falsely negative (ie
negative in the presence of infection), then direct microscopy must be more
sensitive. This is also another example of the problem discussed in Q13.
• 15) It is good practise to always use a selective and non selective medium
when culturing lesions thought to be caused by dermatophytes. Why ?
• If all dermatophytes are resistant to cyclohexamide then why not use just
selective media (containing cyclohexamide) when culturing specimens from
lesions suspected to be caused by dermatophytes?
•
• Well, this concept was alluded to in the last part of the answer to Q8.
Because dermatophytes are the most common isolates from cutaneous
lesions, it is hard not to develop "tunnel vision", or should that be
"dermatophyte vision". Remember that other fungi, most of which are
sensitive to cyclohexamide, can occasionally cause infections that resemble
dermatophytosis. If we only used