Desmoglein-2

Last updated
DSG2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DSG2 , ARVC10, ARVD10, CDHF5, CMD1BB, HDGC, desmoglein 2
External IDs OMIM: 125671 MGI: 1196466 HomoloGene: 1464 GeneCards: DSG2
Orthologs
SpeciesHumanMouse
Entrez

1829

13511

Ensembl

ENSG00000046604

ENSMUSG00000044393

UniProt

Q14126

O55111

RefSeq (mRNA)

NM_001943

NM_007883

RefSeq (protein)

NP_001934

NP_031909

Location (UCSC) Chr 18: 31.5 – 31.55 Mb Chr 18: 20.69 – 20.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. [5] [6] Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy. [7]

Contents

Structure

Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids. [8] Desmoglein-2 is a calcium-binding transmembrane glycoprotein component of desmosomes in vertebrate cells. Currently, four desmoglein subfamily members have been identified and all are members of the cadherin cell adhesion 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-containing tissues, such as cardiac muscle, colon, colon carcinoma, and other simple and stratified epithelial-derived cell lines. [6] Desmoglein-2 is the only desmoglein isoform expressed in cardiomyocytes.

Function

Desmoglein-2 is an integral component of desmosomes, which are cell-cell junctions between epithelial, myocardial, and certain other cell types. Desmogleins and desmocollins connect extracellularly via homophilic and heterophilic interactions. The cytoplasmic tails of desmosomal cadherins bind to plakoglobin and plakophilins, which bind desmoplakin. [9] In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes. [10] In vitro studies in HL-1 cardiomyocytes have shown that inhibition of desmoglein-2 binding or mutation of desmoglein-2 protein (Ala517Val or Val920Gly) at cardiac intercalated discs results in a reduced strength of cell-cell contact, demonstrating that desmoglein-2 is critical for cardiomyocyte cohesion. [11]

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. [12] These mice exhibited white plaque-like lesions in cardiac muscle as early as 2 weeks, displaying a cardiac phenotype by 4 weeks that involved loss of viable cardiomyocytes and heavy cell calcification. Other abnormalities included near to complete dissociation of intercalated discs and inflammation, and eventual arrhythmogenic right ventricular cardiomyopathy with ventricular dilation, fibrosis and cardiac arrhythmia. Studies employing another transgenic mutant DSG2 mouse model harboring an Asn271Ser showed that this mutation caused widening of desmosomes and adherens junctions concomitant with electrophysiologic abnormalities and enhanced susceptibility to cardiac arrhythmias. [13] These changes occurred prior to any cardiomyocyte necrosis or fibrosis. Additionally, it was demonstrated that desmoglein-2 interacts in vivo with the sodium channel protein Na(V)1.5. [13] An additional transgenic model in which desmoglein-2 was knocked out in a cardiac-specific manner showed a loss of adhesive function at intercalated discs in adult animals, albeit normal heart development. In adulthood, 100% of transgenic mutant mice developed chamber dilation, necrosis, aseptic inflammation, fibrosis and conduction defects, as well as modified distribution of connexin-43. [14]

Clinical significance

Mutations in DSG2 have been identified in patients with arrhythmogenic right ventricular cardiomyopathy, [15] along with other desmosomal proteins PKP2 and DSP. Ultrastructural analysis has identified the presence of intercalated disc remodeling in these patients. [16] Additionally, the Val55Met mutation in DSG2 was identified as a novel risk variant for familial dilated cardiomyopathy; patients carrying this mutation exhibited shortened desmosomal structures at cardiac intercalated discs compared to non-diseased patients. [17]

Interactions

Desmoglein-2 has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">Desmosome</span> Cell junction involved in cell-to-cell adhesion

A desmosome, also known as a macula adherens, is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes. Desmosomes are one of the stronger cell-to-cell adhesion types and are found in tissue that experience intense mechanical stress, such as cardiac muscle tissue, bladder tissue, gastrointestinal mucosa, and epithelia.

<span class="mw-page-title-main">Arrhythmogenic cardiomyopathy</span> Medical condition

Arrhythmogenic cardiomyopathy (ACM), arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC), most commonly is an inherited heart disease.

<span class="mw-page-title-main">Cadherin</span>

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+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.

<span class="mw-page-title-main">Desmin</span> Mammalian protein found in humans

Desmin is a protein that in humans is encoded by the DES gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture.

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.

<span class="mw-page-title-main">Desmoglein-1</span> Protein found in humans

Desmoglein-1 is a protein that in humans is encoded by the DSG1 gene. Desmoglein-1 is expressed everywhere in the skin epidermis, but mainly it is expressed in the superficial upper layers of the skin epidermis.

<span class="mw-page-title-main">Desmoglein-3</span> Protein found in humans

Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene. In the skin epidermis Desmoglein-3 is expressed in the basal lower layers of the epidermis, and dominates in terms of expression on mucosal surfaces compared to Desmoglein-1.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in Homo sapiens

Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">Desmoplakin</span> Protein found in humans

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 contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury; striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.

<span class="mw-page-title-main">Plakoglobin</span> Mammalian protein found in Homo sapiens

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 component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

<span class="mw-page-title-main">Cadherin-2</span> Protein-coding gene in the species Homo sapiens

Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

<span class="mw-page-title-main">DSC2</span> Protein-coding gene in humans

Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene. Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">DSC1</span> Protein-coding gene in the species Homo sapiens

Desmocollin-1 is a protein that in humans is encoded by the DSC1 gene.

<span class="mw-page-title-main">Plakophilin-1</span> Protein-coding gene in the species Homo sapiens

Plakophilin-1 is a protein that in humans is encoded by the PKP1 gene.

<span class="mw-page-title-main">DSC3</span> Protein-coding gene in the species Homo sapiens

Desmocollin-3 is a protein that in humans is encoded by the DSC3 gene.

<span class="mw-page-title-main">Plakophilin-2</span> Protein-coding gene in the species Homo sapiens

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-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">Plakophilin-3</span> Protein-coding gene in the species Homo sapiens

Plakophilin-3 is a protein that in humans is encoded by the PKP3 gene.

<span class="mw-page-title-main">Catenin alpha-1</span> Protein-coding gene in the species Homo sapiens

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

Desmocollins are a subfamily of desmosomal cadherins, the transmembrane constituents of desmosomes. They are co-expressed with desmogleins to link adjacent cells by extracellular adhesion. There are seven desmosomal cadherins in humans, three desmocollins and four desmogleins. Desmosomal cadherins allow desmosomes to contribute to the integrity of tissue structure in multicellular living organisms.

Plakophilin are proteins of the cytoskeleton. They are involved in regulating the adhesive activity of cadherin.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000046604 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000044393 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Arnemann J, Spurr NK, Magee AI, Buxton RS (Jun 1992). "The human gene (DSG2) coding for HDGC, a second member of the desmoglein subfamily of the desmosomal cadherins, is, like DSG1 coding for desmoglein DGI, assigned to chromosome 18". Genomics. 13 (2): 484–6. doi:10.1016/0888-7543(92)90280-6. PMID   1612610.
  6. 1 2 "Entrez Gene: DSG2 desmoglein 2".
  7. ↑ Brodehl, Andreas; Meshkov, Alexey; Myasnikov, Roman; Kiseleva, Anna; Kulikova, Olga; Klauke, Bärbel; Sotnikova, Evgeniia; Stanasiuk, Caroline; Divashuk, Mikhail; Pohl, Greta Marie; Kudryavtseva, Maria (2021-04-06). "Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset". International Journal of Molecular Sciences. 22 (7): 3786. doi: 10.3390/ijms22073786 . ISSN   1422-0067. PMC   8038858 . PMID   33917638.
  8. ↑ "Protein sequence of human DSG2 protein". Cardiac Organellar Protein Atlas Knowledgebase. Archived from the original on 4 March 2016. Retrieved 15 September 2015.
  9. ↑ Li J, Radice GL (2010). "A new perspective on intercalated disc organization: implications for heart disease". Dermatology Research and Practice. 2010: 207835. doi: 10.1155/2010/207835 . PMC   2879923 . PMID   20585598.
  10. ↑ Franke WW, Borrmann CM, Grund C, Pieperhoff S (Feb 2006). "The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins". European Journal of Cell Biology. 85 (2): 69–82. doi:10.1016/j.ejcb.2005.11.003. PMID   16406610.
  11. ↑ Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, Mckenna WJ, Dendorfer A, Hartlieb E, Waschke J (Nov 2014). "Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function". Cardiovascular Research. 104 (2): 245–57. doi: 10.1093/cvr/cvu206 . PMID   25213555.
  12. ↑ Kant S, Krull P, Eisner S, Leube RE, Krusche CA (May 2012). "Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts". Cell and Tissue Research. 348 (2): 249–59. doi:10.1007/s00441-011-1322-3. PMID   22293975. S2CID   14574561.
  13. 1 2 3 Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L, Pilichou K, Basso C, Remme CA, Thiene G, Bezzina CR (Sep 2012). "Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes". Cardiovascular Research. 95 (4): 409–18. doi: 10.1093/cvr/cvs219 . PMID   22764152.
  14. ↑ Kant S, Holthöfer B, Magin TM, Krusche CA, Leube RE (Aug 2015). "Desmoglein 2-Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function". Circulation: Cardiovascular Genetics. 8 (4): 553–63. doi: 10.1161/CIRCGENETICS.114.000974 . PMID   26085008.
  15. ↑ Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (Mar 2006). "Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy". Circulation. 113 (9): 1171–9. doi: 10.1161/CIRCULATIONAHA.105.583674 . PMID   16505173.
  16. ↑ Basso C, Czarnowska E, Della Barbera M, Bauce B, Beffagna G, Wlodarska EK, Pilichou K, Ramondo A, Lorenzon A, Wozniek O, Corrado D, Daliento L, Danieli GA, Valente M, Nava A, Thiene G, Rampazzo A (Aug 2006). "Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies". European Heart Journal. 27 (15): 1847–54. doi: 10.1093/eurheartj/ehl095 . PMID   16774985.
  17. ↑ Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, Ruppert V, Pankuweit S, Maisch B, Perrot A, Buttgereit J, Dietz R, Haverkamp W, Ozcelik C (Sep 2008). "A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy". Molecular Genetics and Metabolism. 95 (1–2): 74–80. doi:10.1016/j.ymgme.2008.06.005. PMID   18678517.
  18. ↑ Chitaev NA, Troyanovsky SM (Jul 1997). "Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion". The Journal of Cell Biology. 138 (1): 193–201. doi:10.1083/jcb.138.1.193. PMC   2139935 . PMID   9214392.
  19. ↑ Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F (Apr 2003). "Defining desmosomal plakophilin-3 interactions". The Journal of Cell Biology. 161 (2): 403–16. doi:10.1083/jcb.200303036. PMC   2172904 . PMID   12707304.
  20. ↑ Bannon LJ, Cabrera BL, Stack MS, Green KJ (Nov 2001). "Isoform-specific differences in the size of desmosomal cadherin/catenin complexes". The Journal of Investigative Dermatology. 117 (5): 1302–6. doi: 10.1046/j.1523-1747.2001.01512.x . PMID   11710948.
  21. ↑ Nieset JE, Sacco-Bubulya PA, Sadler TM, Johnson KR, Wheelock MJ (May 2000). "The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2". Journal of Cell Science. 113 (10): 1737–45. doi: 10.1242/jcs.113.10.1737 . PMID   10769205.
  22. ↑ Ozawa M, Terada H, Pedraza C (Nov 1995). "The fourth armadillo repeat of plakoglobin (gamma-catenin) is required for its high affinity binding to the cytoplasmic domains of E-cadherin and desmosomal cadherin Dsg2, and the tumor suppressor APC protein". Journal of Biochemistry. 118 (5): 1077–82. doi:10.1093/jb/118.5.1077. PMID   8749329.

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