Desmoglein-2 is a 122.2 kDa protein composed of 1118 amino acids.[3] 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 cadherincell 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.[4] In cardiac muscle, desmoglein-2 localizes to the intercalated disc, responsible for mechanically and electrically coupling adjacent cardiomyocytes.[5] 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.[6]
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.[7] 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 a Asn271Ser showed that this mutation caused widening of desmosomes and adherens junctions concomitant with electrophysiologic abnormalities and enhanced susceptibility to cardiac arrhythmias.[8] These changes occurred prior to any cardiomyocytenecrosis or fibrosis. Additionally, it was demonstrated that desmoglein-2 interacts in vivo with the sodium channel protein Na(V)1.5.[8] 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.[9]
↑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. PMID1612610.
↑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. PMID16406610.
↑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. PMID25213555.
↑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. PMID22293975.
↑ 8.08.18.2Rizzo 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. PMID22764152.
↑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. PMID26085008.
↑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. PMID16505173.
↑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. PMID16774985.
↑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. PMID18678517.
↑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. PMID11710948.
↑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. PMID10769205.
↑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. PMID8749329.
Further reading
Koch PJ, Goldschmidt MD, Walsh MJ, Zimbelmann R, Franke WW (Aug 1991). "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. PMID1935985.
Simrak D, Cowley CM, Buxton RS, Arnemann J (Jan 1995). "Tandem arrangement of the closely linked desmoglein genes on human chromosome 18". Genomics. 25 (2): 591–4. doi:10.1016/0888-7543(95)80067-V. PMID7790000.
Schäfer S, Koch PJ, Franke WW (Apr 1994). "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. doi:10.1006/excr.1994.1103. PMID8143788.
Schäfer S, Stumpp S, Franke WW (May 1996). "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. doi:10.1046/j.1432-0436.1996.6020099.x. PMID8641550.
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. PMID8749329.
Denning MF, Guy SG, Ellerbroek SM, Norvell SM, Kowalczyk AP, Green KJ (Feb 1998). "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. doi:10.1006/excr.1997.3890. PMID9511724.
Moll I, Houdek P, Schäfer S, Nuber U, Moll R (1999). "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. doi:10.1007/s004030050435. PMID10482015.
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. PMID10769205.
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. PMID11710948.
Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ (Mar 2002). "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. doi:10.1074/jbc.M108765200. PMID11790773.
Zhang H, Li XJ, Martin DB, Aebersold R (Jun 2003). "Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry". Nature Biotechnology. 21 (6): 660–6. doi:10.1038/nbt827. PMID12754519.
Wu H, Stanley JR, Cotsarelis G (Jun 2003). "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. doi:10.1046/j.1523-1747.2003.12234.x. PMID12787134.
Amanchy R, Kalume DE, Iwahori A, Zhong J, Pandey A (2006). "Phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture (SILAC)". Journal of Proteome Research. 4 (5): 1661–71. doi:10.1021/pr050134h. PMID16212419.