Biology:Desmoglein-2

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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:


See also

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

References

  1. ↑ "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. doi:10.1016/0888-7543(92)90280-6. PMID 1612610. 
  2. ↑ 2.0 2.1 "Entrez Gene: DSG2 desmoglein 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1829. 
  3. ↑ Brodehl, Andreas; Meshkov, Alexey; Myasnikov, Roman; Kiseleva, Anna; Kulikova, Olga; Klauke, Bärbel; Sotnikova, Evgeniia; Stanasiuk, Caroline et al. (2021-04-06). "Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset" (in en). International Journal of Molecular Sciences 22 (7): 3786. doi:10.3390/ijms22073786. ISSN 1422-0067. PMID 33917638. 
  4. ↑ "Protein sequence of human DSG2 protein". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14126. 
  5. ↑ "A new perspective on intercalated disc organization: implications for heart disease". Dermatology Research and Practice 2010: 207835. 2010. doi:10.1155/2010/207835. PMID 20585598. 
  6. ↑ "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. doi:10.1016/j.ejcb.2005.11.003. PMID 16406610. 
  7. ↑ "Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function". Cardiovascular Research 104 (2): 245–57. Nov 2014. doi:10.1093/cvr/cvu206. PMID 25213555. 
  8. ↑ "Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts". Cell and Tissue Research 348 (2): 249–59. May 2012. doi:10.1007/s00441-011-1322-3. PMID 22293975. 
  9. ↑ 9.0 9.1 9.2 "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. doi:10.1093/cvr/cvs219. PMID 22764152. 
  10. ↑ "Desmoglein 2-Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function". Circulation: Cardiovascular Genetics 8 (4): 553–63. Aug 2015. doi:10.1161/CIRCGENETICS.114.000974. PMID 26085008. 
  11. ↑ "Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy". Circulation 113 (9): 1171–9. Mar 2006. doi:10.1161/CIRCULATIONAHA.105.583674. PMID 16505173. 
  12. ↑ "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. doi:10.1093/eurheartj/ehl095. PMID 16774985. 
  13. ↑ "A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy". Molecular Genetics and Metabolism 95 (1–2): 74–80. Sep 2008. doi:10.1016/j.ymgme.2008.06.005. PMID 18678517. 
  14. ↑ "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. doi:10.1083/jcb.138.1.193. PMID 9214392. 
  15. ↑ "Defining desmosomal plakophilin-3 interactions". The Journal of Cell Biology 161 (2): 403–16. Apr 2003. doi:10.1083/jcb.200303036. PMID 12707304. 
  16. ↑ "Isoform-specific differences in the size of desmosomal cadherin/catenin complexes". The Journal of Investigative Dermatology 117 (5): 1302–6. Nov 2001. doi:10.1046/j.1523-1747.2001.01512.x. PMID 11710948. 
  17. ↑ "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. doi:10.1242/jcs.113.10.1737. PMID 10769205. 
  18. ↑ "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. doi:10.1093/jb/118.5.1077. PMID 8749329. 

Further reading

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