Desmoglein-2

DSG2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2YQG, 5ERD, 5J5J
Identifiers
Aliases	DSG2 , ARVC10, ARVD10, CDHF5, CMD1BB, HDGC, desmoglein 2
External IDs	OMIM: 125671; MGI: 1196466; HomoloGene: 1464; GeneCards: DSG2; OMA:DSG2 - orthologs
Gene location (Human) Chr. Chromosome 18 (human) [1] Band 18q12.1 Start 31,498,177 bp [1] End 31,549,008 bp [1]
Gene location (Mouse) Chr. Chromosome 18 (mouse) [2] Band 18 A2|18 11.42 cM Start 20,691,131 bp [2] End 20,737,578 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of sigmoid colon jejunal mucosa palpebral conjunctiva parotid gland hair follicle rectum lactiferous duct Epithelium of choroid plexus duodenum germinal epithelium Top expressed in left colon transitional epithelium of urinary bladder parotid gland epithelium of stomach Paneth cell crypt of lieberkuhn of small intestine lacrimal gland submandibular gland pyloric antrum mucous cell of stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding metal ion binding cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication cell adhesion molecule binding Cellular component integral component of membrane lateral plasma membrane membrane intercalated disc cell-cell junction plasma membrane desmosome cell surface cell junction apical plasma membrane extracellular exosome cornified envelope intracellular membrane-bounded organelle Biological process desmosome organization maternal process involved in female pregnancy response to progesterone bundle of His cell-Purkinje myocyte adhesion involved in cell communication cell adhesion Purkinje myocyte development regulation of heart rate by cardiac conduction regulation of ventricular cardiac muscle cell action potential homophilic cell adhesion via plasma membrane adhesion molecules keratinization cornification cell-cell adhesion Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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]

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:

• DSC1 ^[18]
• PKP3 ^[19]
• Plakoglobin ^{[20] [21] [22]} and
• SCN5A ^[13]

See also

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

References

1. GRCh38: Ensembl release 89: ENSG00000046604 – Ensembl, May 2017
2. 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. "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. 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 . hdl: 11577/2434417 . 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 . hdl: 11577/2434507 . 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.

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. PMID   1935985.
• 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. PMID   7790000.
• 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. PMID   8143788.
• 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. PMID   8641550.
• 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.
• 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.
• 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 . PMID   9511724.
• Krunic AL, Garrod DR, Madani S, Buchanan MD, Clark RE (Apr 1998). "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. doi:10.1038/bjc.1998.213. PMC   2150164 . PMID   9579833.
• 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. PMID   10482015. S2CID   6183331.
• 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.
• 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.
• 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 . PMID   11790773.
• Syed SE, Trinnaman B, Martin S, Major S, Hutchinson J, Magee AI (Mar 2002). "Molecular interactions between desmosomal cadherins". The Biochemical Journal. 362 (Pt 2): 317–27. doi:10.1042/0264-6021:3620317. PMC   1222391 . PMID   11853539.
• 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.
• 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. PMID   12754519. S2CID   581283.
• 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 . PMID   12787134.
• Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S (Sep 2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC   515316 . PMID   15342556.
• 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. PMID   16212419.

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
• Overview of all the structural information available in the PDB for UniProt : Q14126 (Desmoglein-2) at the PDBe-KB .