Desmoglein-2

Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids.{{cite web|title=Protein sequence of human DSG2 protein|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14126|website=Cardiac Organellar Protein Atlas Knowledgebase|access-date=15 September 2015|archive-url=https://web.archive.org/web/20160304094802/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14126|archive-date=4 March 2016|url-status=dead}} 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. Desmoglein-2 is the only desmoglein isoform expressed in cardiomyocytes.

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.{{cite journal | vauthors = Li J, Radice GL | title = A new perspective on intercalated disc organization: implications for heart disease | journal = Dermatology Research and Practice | volume = 2010 | pages = 207835 | date = 2010 | pmid = 20585598 | doi = 10.1155/2010/207835 | pmc=2879923| doi-access = free }} In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes.{{cite journal | vauthors = Franke WW, Borrmann CM, Grund C, Pieperhoff S | title = 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 | journal = European Journal of Cell Biology | volume = 85 | issue = 2 | pages = 69–82 | date = Feb 2006 | pmid = 16406610 | doi = 10.1016/j.ejcb.2005.11.003 }} 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.{{cite journal | vauthors = Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, Mckenna WJ, Dendorfer A, Hartlieb E, Waschke J | title = Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function | journal = Cardiovascular Research | volume = 104 | issue = 2 | pages = 245–57 | date = Nov 2014 | pmid = 25213555 | doi = 10.1093/cvr/cvu206 | doi-access = free }}

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.{{cite journal | vauthors = Kant S, Krull P, Eisner S, Leube RE, Krusche CA | title = Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts | journal = Cell and Tissue Research | volume = 348 | issue = 2 | pages = 249–59 | date = May 2012 | pmid = 22293975 | doi = 10.1007/s00441-011-1322-3 | s2cid = 14574561 }} 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.{{cite journal | vauthors = Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L, Pilichou K, Basso C, Remme CA, Thiene G, Bezzina CR | title = Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes | journal = Cardiovascular Research | volume = 95 | issue = 4 | pages = 409–18 | date = Sep 2012 | pmid = 22764152 | doi = 10.1093/cvr/cvs219 | doi-access = free }} 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. 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.{{cite journal | vauthors = Kant S, Holthöfer B, Magin TM, Krusche CA, Leube RE | title = Desmoglein 2-Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function | journal = Circulation: Cardiovascular Genetics | volume = 8 | issue = 4 | pages = 553–63 | date = Aug 2015 | pmid = 26085008 | doi = 10.1161/CIRCGENETICS.114.000974 | doi-access = free }}

Mutations in DSG2 have been identified in patients with arrhythmogenic right ventricular cardiomyopathy,{{cite journal | vauthors = 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 | title = Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy | journal = Circulation | volume = 113 | issue = 9 | pages = 1171–9 | date = Mar 2006 | pmid = 16505173 | doi = 10.1161/CIRCULATIONAHA.105.583674 | doi-access = free | hdl = 11577/2434417 | hdl-access = free }} along with other desmosomal proteins PKP2 and DSP. Ultrastructural analysis has identified the presence of intercalated disc remodeling in these patients.{{cite journal | vauthors = 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 | title = Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies | journal = European Heart Journal | volume = 27 | issue = 15 | pages = 1847–54 | date = Aug 2006 | pmid = 16774985 | doi = 10.1093/eurheartj/ehl095 | doi-access = free | hdl = 11577/2434507 | hdl-access = free }} 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.{{cite journal | vauthors = 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 | title = A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy | journal = Molecular Genetics and Metabolism | volume = 95 | issue = 1–2 | pages = 74–80 | date = Sep 2008 | pmid = 18678517 | doi = 10.1016/j.ymgme.2008.06.005 }}

Desmoglein-2 has been shown to interact with:

• DSC1{{cite journal | vauthors = Chitaev NA, Troyanovsky SM | title = Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion | journal = The Journal of Cell Biology | volume = 138 | issue = 1 | pages = 193–201 | date = Jul 1997 | pmid = 9214392 | pmc = 2139935 | doi = 10.1083/jcb.138.1.193 }}
• PKP3{{cite journal | vauthors = Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F | title = Defining desmosomal plakophilin-3 interactions | journal = The Journal of Cell Biology | volume = 161 | issue = 2 | pages = 403–16 | date = Apr 2003 | pmid = 12707304 | pmc = 2172904 | doi = 10.1083/jcb.200303036 }}
• Plakoglobin{{cite journal | vauthors = Bannon LJ, Cabrera BL, Stack MS, Green KJ | title = Isoform-specific differences in the size of desmosomal cadherin/catenin complexes | journal = The Journal of Investigative Dermatology | volume = 117 | issue = 5 | pages = 1302–6 | date = Nov 2001 | pmid = 11710948 | doi = 10.1046/j.1523-1747.2001.01512.x | doi-access = free }}{{cite journal | vauthors = Nieset JE, Sacco-Bubulya PA, Sadler TM, Johnson KR, Wheelock MJ | title = The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2 | journal = Journal of Cell Science | volume = 113 | issue = 10 | pages = 1737–45 | date = May 2000 | doi = 10.1242/jcs.113.10.1737 | pmid = 10769205 | doi-access = free }}{{cite journal | vauthors = Ozawa M, Terada H, Pedraza C | title = 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 = Journal of Biochemistry | volume = 118 | issue = 5 | pages = 1077–82 | date = Nov 1995 | pmid = 8749329 | doi = 10.1093/jb/118.5.1077 }} and
• SCN5A

• Desmoglein
• List of conditions caused by problems with junctional proteins

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{{refbegin|33em}}

• {{cite journal | vauthors = Koch PJ, Goldschmidt MD, Walsh MJ, Zimbelmann R, Franke WW | title = Complete amino acid sequence of the epidermal desmoglein precursor polypeptide and identification of a second type of desmoglein gene | journal = European Journal of Cell Biology | volume = 55 | issue = 2 | pages = 200–8 | date = Aug 1991 | pmid = 1935985 }}
• {{cite journal | vauthors = Simrak D, Cowley CM, Buxton RS, Arnemann J | title = Tandem arrangement of the closely linked desmoglein genes on human chromosome 18 | journal = Genomics | volume = 25 | issue = 2 | pages = 591–4 | date = Jan 1995 | pmid = 7790000 | doi = 10.1016/0888-7543(95)80067-V }}
• {{cite journal | vauthors = Schäfer S, Koch PJ, Franke WW | title = Identification of the ubiquitous human desmoglein, Dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins | journal = Experimental Cell Research | volume = 211 | issue = 2 | pages = 391–9 | date = Apr 1994 | pmid = 8143788 | doi = 10.1006/excr.1994.1103 }}
• {{cite journal | vauthors = Schäfer S, Stumpp S, Franke WW | title = Immunological identification and characterization of the desmosomal cadherin Dsg2 in coupled and uncoupled epithelial cells and in human tissues | journal = Differentiation; Research in Biological Diversity | volume = 60 | issue = 2 | pages = 99–108 | date = May 1996 | pmid = 8641550 | doi = 10.1046/j.1432-0436.1996.6020099.x }}
• {{cite journal | vauthors = Ozawa M, Terada H, Pedraza C | title = 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 = Journal of Biochemistry | volume = 118 | issue = 5 | pages = 1077–82 | date = Nov 1995 | pmid = 8749329 | doi = 10.1093/jb/118.5.1077 }}
• {{cite journal | vauthors = Chitaev NA, Troyanovsky SM | title = Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion | journal = The Journal of Cell Biology | volume = 138 | issue = 1 | pages = 193–201 | date = Jul 1997 | pmid = 9214392 | pmc = 2139935 | doi = 10.1083/jcb.138.1.193 }}
• {{cite journal | vauthors = Denning MF, Guy SG, Ellerbroek SM, Norvell SM, Kowalczyk AP, Green KJ | title = The expression of desmoglein isoforms in cultured human keratinocytes is regulated by calcium, serum, and protein kinase C | journal = Experimental Cell Research | volume = 239 | issue = 1 | pages = 50–9 | date = Feb 1998 | pmid = 9511724 | doi = 10.1006/excr.1997.3890 | doi-access = free }}
• {{cite journal | vauthors = Krunic AL, Garrod DR, Madani S, Buchanan MD, Clark RE | title = Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin | journal = British Journal of Cancer | volume = 77 | issue = 8 | pages = 1275–9 | date = Apr 1998 | pmid = 9579833 | pmc = 2150164 | doi = 10.1038/bjc.1998.213 }}
• {{cite journal | vauthors = Moll I, Houdek P, Schäfer S, Nuber U, Moll R | title = Diversity of desmosomal proteins in regenerating epidermis: immunohistochemical study using a human skin organ culture model | journal = Archives of Dermatological Research | volume = 291 | issue = 7–8 | pages = 437–46 | year = 1999 | pmid = 10482015 | doi = 10.1007/s004030050435 | s2cid = 6183331 }}
• {{cite journal | vauthors = Nieset JE, Sacco-Bubulya PA, Sadler TM, Johnson KR, Wheelock MJ | title = The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2 | journal = Journal of Cell Science | volume = 113 | issue = 10 | pages = 1737–45 | date = May 2000 | doi = 10.1242/jcs.113.10.1737 | pmid = 10769205 | doi-access = free }}
• {{cite journal | vauthors = Bannon LJ, Cabrera BL, Stack MS, Green KJ | title = Isoform-specific differences in the size of desmosomal cadherin/catenin complexes | journal = The Journal of Investigative Dermatology | volume = 117 | issue = 5 | pages = 1302–6 | date = Nov 2001 | pmid = 11710948 | doi = 10.1046/j.1523-1747.2001.01512.x | doi-access = free }}
• {{cite journal | vauthors = Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ | title = Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10512–22 | date = Mar 2002 | pmid = 11790773 | doi = 10.1074/jbc.M108765200 | doi-access = free }}
• {{cite journal | vauthors = Syed SE, Trinnaman B, Martin S, Major S, Hutchinson J, Magee AI | title = Molecular interactions between desmosomal cadherins | journal = The Biochemical Journal | volume = 362 | issue = Pt 2 | pages = 317–27 | date = Mar 2002 | pmid = 11853539 | pmc = 1222391 | doi = 10.1042/0264-6021:3620317 }}
• {{cite journal | vauthors = Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F | title = Defining desmosomal plakophilin-3 interactions | journal = The Journal of Cell Biology | volume = 161 | issue = 2 | pages = 403–16 | date = Apr 2003 | pmid = 12707304 | pmc = 2172904 | doi = 10.1083/jcb.200303036 }}
• {{cite journal | vauthors = Zhang H, Li XJ, Martin DB, Aebersold R | title = Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry | journal = Nature Biotechnology | volume = 21 | issue = 6 | pages = 660–6 | date = Jun 2003 | pmid = 12754519 | doi = 10.1038/nbt827 | s2cid = 581283 }}
• {{cite journal | vauthors = Wu H, Stanley JR, Cotsarelis G | title = Desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation | journal = The Journal of Investigative Dermatology | volume = 120 | issue = 6 | pages = 1052–7 | date = Jun 2003 | pmid = 12787134 | doi = 10.1046/j.1523-1747.2003.12234.x | doi-access = free }}
• {{cite journal | vauthors = Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S | title = Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions | journal = Genome Research | volume = 14 | issue = 9 | pages = 1711–8 | date = Sep 2004 | pmid = 15342556 | pmc = 515316 | doi = 10.1101/gr.2435604 }}
• {{cite journal | vauthors = Amanchy R, Kalume DE, Iwahori A, Zhong J, Pandey A | title = Phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture (SILAC) | journal = Journal of Proteome Research | volume = 4 | issue = 5 | pages = 1661–71 | year = 2006 | pmid = 16212419 | doi = 10.1021/pr050134h }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1131/ GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant]
• [https://www.ncbi.nlm.nih.gov/omim/604772,605676,601214,107970,125645,125647,125671,173325,180902,190230,600996,602086,602087,602861,604400,604401,607450,609040,609160,610193,610476,611528,612048,107970,125645,125647,125671,173325,180902,190230,600996,602086,602087,602861,604400,604401,607450,609040,609160,610193,610476,611528,612048 OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant]
• {{PDBe-KB2|Q14126|Desmoglein-2}}

{{Cell adhesion molecules}}