Wikipedia

Desmoglein-2

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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]

DSG2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDSG2, ARVC10, ARVD10, CDHF5, CMD1BB, HDGC, desmoglein 2
External IDsOMIM: 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 MbChr 18: 20.69 – 20.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure edit

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 edit

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 edit

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 edit

Desmoglein-2 has been shown to interact with:

See also edit

References edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000046604 - Ensembl, May 2017
  2. ^ a b c 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. ^ a b "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. ^ a b c 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.

Further reading edit

External links edit

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