Desmoglein-2 Explained

Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene.^{[1] [2]} 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.^[3]

Structure

Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids.^[4] 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.^[2] 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.^[5] In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes.^[6] 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.^[7]

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.^[8] 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.^[9] 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.^[9] 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.^[10]

Clinical significance

Mutations in DSG2 have been identified in patients with arrhythmogenic right ventricular cardiomyopathy,^[11] along with other desmosomal proteins PKP2 and DSP. Ultrastructural analysis has identified the presence of intercalated disc remodeling in these patients.^[12] 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.^[13]

Interactions

Desmoglein-2 has been shown to interact with:

• DSC1^[14]
• PKP3^[15]
• Plakoglobin^{[16] [17] [18]} and
• SCN5A^[9]

See also

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

Further reading

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

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

Notes and References

1. Arnemann J, Spurr NK, Magee AI, Buxton RS . 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 . Jun 1992 . 1612610 . 10.1016/0888-7543(92)90280-6 .
2. Web site: Entrez Gene: DSG2 desmoglein 2.
3. 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. en. 22. 7. 3786. 10.3390/ijms22073786. 33917638. 8038858. 1422-0067. free.
4. Web site: Protein sequence of human DSG2 protein. Cardiac Organellar Protein Atlas Knowledgebase. 15 September 2015. https://web.archive.org/web/20160304094802/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14126. 4 March 2016. dead.
5. Li J, Radice GL . A new perspective on intercalated disc organization: implications for heart disease . Dermatology Research and Practice . 2010 . 207835 . 2010 . 20585598 . 10.1155/2010/207835 . 2879923. free .
6. Franke WW, Borrmann CM, Grund C, Pieperhoff S . 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 . Feb 2006 . 16406610 . 10.1016/j.ejcb.2005.11.003 .
7. Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, Mckenna WJ, Dendorfer A, Hartlieb E, Waschke J . Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function . Cardiovascular Research . 104 . 2 . 245–57 . Nov 2014 . 25213555 . 10.1093/cvr/cvu206 . free .
8. Kant S, Krull P, Eisner S, Leube RE, Krusche CA . Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts . Cell and Tissue Research . 348 . 2 . 249–59 . May 2012 . 22293975 . 10.1007/s00441-011-1322-3 . 14574561 .
9. Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L, Pilichou K, Basso C, Remme CA, Thiene G, Bezzina CR . 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 . Sep 2012 . 22764152 . 10.1093/cvr/cvs219 . free .
10. Kant S, Holthöfer B, Magin TM, Krusche CA, Leube RE . Desmoglein 2-Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function . Circulation: Cardiovascular Genetics . 8 . 4 . 553–63 . Aug 2015 . 26085008 . 10.1161/CIRCGENETICS.114.000974 . free .
11. 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 . Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy . Circulation . 113 . 9 . 1171–9 . Mar 2006 . 16505173 . 10.1161/CIRCULATIONAHA.105.583674 . free . 11577/2434417 . free .
12. 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 . 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 . Aug 2006 . 16774985 . 10.1093/eurheartj/ehl095 . free . 11577/2434507 . free .
13. 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 . A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy . Molecular Genetics and Metabolism . 95 . 1–2 . 74–80 . Sep 2008 . 18678517 . 10.1016/j.ymgme.2008.06.005 .
14. Chitaev NA, Troyanovsky SM . 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 . Jul 1997 . 9214392 . 2139935 . 10.1083/jcb.138.1.193 .
15. Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F . Defining desmosomal plakophilin-3 interactions . The Journal of Cell Biology . 161 . 2 . 403–16 . Apr 2003 . 12707304 . 2172904 . 10.1083/jcb.200303036 .
16. Bannon LJ, Cabrera BL, Stack MS, Green KJ . Isoform-specific differences in the size of desmosomal cadherin/catenin complexes . The Journal of Investigative Dermatology . 117 . 5 . 1302–6 . Nov 2001 . 11710948 . 10.1046/j.1523-1747.2001.01512.x . free .
17. Nieset JE, Sacco-Bubulya PA, Sadler TM, Johnson KR, Wheelock MJ . The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2 . Journal of Cell Science . 113 . 10 . 1737–45 . May 2000 . 10.1242/jcs.113.10.1737 . 10769205 . free .
18. Ozawa M, Terada H, Pedraza C . 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 . Nov 1995 . 8749329 . 10.1093/jb/118.5.1077 .