HOME

TheInfoList



OR:

Desmoglein-2 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''DSG2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Desmoglein-2 is highly expressed in
epithelial cell Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...
s and
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s. Desmoglein-2 is localized to
desmosome A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like ad ...
structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In
cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
, these regions are specialized regions known as
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
s. Mutations in desmoglein-2 have been associated with
arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease. ACM is caused by genetic defects of parts of the cardiac muscle known as desmosomes, areas on the surface of muscle cells which link them together. The desmosomes are composed o ...
and familial
dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...
.


Structure

Desmoglein-2 is a 122.2 kDa
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
composed of 1118
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s. Desmoglein-2 is a
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
-binding transmembrane glycoprotein component of desmosomes in vertebrate cells. Currently, four desmoglein subfamily members have been identified and all are members of the
cadherin Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...
cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
molecule superfamily. These desmoglein gene family members are located in a cluster on chromosome 18. This second family member, desmoglein-2 is expressed in
desmosome A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like ad ...
-containing tissues, such as
cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
, colon,
colon carcinoma Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
, and other simple and stratified epithelial-derived cell lines. Desmoglein-2 is the only desmoglein isoform expressed in
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s.


Function

Desmoglein-2 is an integral component of
desmosome A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like ad ...
s, which are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmogleins and desmocollins connect extracellularly via homophilic and heterophilic interactions. The
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
ic tails of desmosomal cadherins bind to
plakoglobin Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the ''JUP'' gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic compon ...
and plakophilins, which bind
desmoplakin Desmoplakin is a protein in humans that is encoded by the ''DSP'' gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell co ...
. In
cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
, desmoglein-2 localizes to the
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
, responsible for mechanically and electrically coupling adjacent
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s. In vitro studies in HL-1
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s have shown that inhibition of desmoglein-2 binding or mutation of desmoglein-2 protein ( Ala517 Val or Val920 Gly) at cardiac
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
s results in a reduced strength of cell-cell contact, demonstrating that desmoglein-2 is critical for
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
cohesion. Studies in transgenic animals have provided insights into desmoglein-2 function. Mice harboring a mutation in ''DSG-2'' in which desmoglein-2 lacked parts of the adhesive extracellular domains were serially examined over time. These mice exhibited white plaque-like lesions in
cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
as early as 2 weeks, displaying a cardiac phenotype by 4 weeks that involved loss of viable
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
s and heavy cell calcification. Other abnormalities included near to complete dissociation of
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
s and
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, and eventual
arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease. ACM is caused by genetic defects of parts of the cardiac muscle known as desmosomes, areas on the surface of muscle cells which link them together. The desmosomes are composed o ...
with ventricular dilation,
fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...
and cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
. Studies employing another transgenic mutant ''DSG2'' mouse model harboring an Asn271 Ser showed that this mutation caused widening of
desmosome A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like ad ...
s and
adherens junctions In cell biology, adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basal ...
concomitant with electrophysiologic abnormalities and enhanced susceptibility to cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s. These changes occurred prior to any
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
or
fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...
. Additionally, it was demonstrated that desmoglein-2 interacts in vivo with the
sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...
protein Na(V)1.5. An additional transgenic model in which desmoglein-2 was knocked out in a cardiac-specific manner showed a loss of adhesive function at
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
s in adult animals, albeit normal heart development. In adulthood, 100% of transgenic mutant mice developed chamber dilation,
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
, aseptic
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...
and conduction defects, as well as modified distribution of
connexin-43 Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the ''GJA1'' gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular c ...
.


Clinical significance

Mutations in ''DSG2'' have been identified in patients with
arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease. ACM is caused by genetic defects of parts of the cardiac muscle known as desmosomes, areas on the surface of muscle cells which link them together. The desmosomes are composed o ...
, along with other desmosomal proteins
PKP2 Plakophilin-2 is a protein that in humans is encoded by the ''PKP2'' gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin- ...
and
DSP DSP may refer to: Computing * Digital signal processing, the mathematical manipulation of an information signal * Digital signal processor, a microprocessor designed for digital signal processing * Dynamic Reconfiguration port * Yamaha DSP-1 ...
. Ultrastructural analysis has identified the presence of
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
remodeling in these patients. Additionally, the Val55 Met mutation in ''DSG2'' was identified as a novel risk variant for familial
dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...
; patients carrying this mutation exhibited shortened desmosomal structures at cardiac
intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional Syncytium#Cardia ...
s compared to non-diseased patients.


Interactions

Desmoglein-2 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with: * DSC1 *
PKP3 Plakophilin-3 is a protein that in humans is encoded by the ''PKP3'' gene. Function This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to ce ...
*
Plakoglobin Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the ''JUP'' gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic compon ...
and *
SCN5A Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of ...


See also

*
Desmoglein The desmogleins are a family of desmosomal cadherins consisting of proteins DSG1, DSG2, DSG3, and DSG4. They play a role in the formation of desmosomes that join cells to one another. Pathology Desmogleins are targeted in the autoimmune disease ...
*
List of conditions caused by problems with junctional proteins A list is a set of discrete items of information collected and set forth in some format for utility, entertainment, or other purposes. A list may be memorialized in any number of ways, including existing only in the mind of the list-maker, but ...


References


Further reading

* * * * * * * * * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
* {{Cell adhesion molecules