Desmoplakin

(Redirected from Desmoplakins)

Desmoplakin is a protein in humans that is encoded by the DSP gene.[5][6][7] Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury;[8][9] striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.

DSP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDSP, DCWHKTA, DP, DPI, DPII, desmoplakin
External IDsOMIM: 125647; MGI: 109611; HomoloGene: 37922; GeneCards: DSP; OMA:DSP - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001008844
NM_004415
NM_001319034

NM_023842

RefSeq (protein)

NP_001008844
NP_001305963
NP_004406

NP_076331

Location (UCSC)Chr 6: 7.54 – 7.59 MbChr 13: 38.34 – 38.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Cell adhesion in desmosomes

Structure

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Desmoplakin exists as two predominant isoforms; the first, known as "DPII", has molecular weight 260.0 kDa (2272 amino acids) and the second, known as "DPI", has molecular weight 332.0 kDa (2871 amino acids).[10][11] These isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant isoform expressed in cardiac muscle.[12] The DSP gene is located on chromosome 6p24.3, containing 24 exons and spanning approximately 45 kDa of genomic DNA.[13] Desmoplakin is a large desmosomal plaque protein that homodimerizes and adopts a dumbbell-shaped conformation.[13] The N-terminal globular head domain of desmoplakin is composed of a series of alpha helical bundles, and is required for both the localization to the desmosome and interaction with the N-terminal region of plakophilin 1 and plakoglobin as well as desmocollin and desmoglein.[14] This is further sub divided into a region called the "Plakin domain" made up of six spectrin repeat domains separated by SH3 domain.[15] A crystal structure of part of the plakin domain has been resolved,[16] while the entire plakin domain has been elucidated using small angle X-ray scattering which revealed a non-linear structure, an unexpected result considering spectrin repeats are observed in linear orientations.[17] The C-terminal region of desmoplakin is composed of three plakin repeat domains, termed A, B and C, which are essential for coalignment and binding of intermediate filaments.[14][18][19] Located at the most distal C-terminus of desmoplakin is a region rich in glycineserinearginine; it has been demonstrated that serine phosphorylation of this domain may modify desmoplakin-intermediate filament interactions.[20] In the mid-region of desmoplakin, a coiled-coil rod domain is responsible for homodimerization.[21]

Function

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Desmosomes are intercellular junctions that tightly link adjacent cells. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. In cardiomyocytes, desmoplakin forms desmosomal plaques with the intermediate filament desmin, whereas in endothelial cells cytokeratin type intermediate filaments are recruited, and vimentin in arachnoid and follicular dendritic cell types.[21][22] Both types of intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque.[23] In cardiac muscle, desmoplakin is localized to desmosomes in intercalated discs. Desmoplakin isoform DPI is highly expressed and is thought to play a role in both the assembly and stabilization of desmosomes; its role is critical, as desmoplakin knockout mice display embryonic lethality.[24] In mice overexpressing a C-terminal mutated desmoplakin protein, desmoplakin binding to desmin is disrupted in cardiac muscle and hearts display abnormal intercalated disc formation and structure.[25] Much has been learned regarding desmoplakin function from mutations in patients with arrhythmogenic right ventricular cardiomyopathy, where mutations in specific binding domains alter desmoplakin binding to plakoglobin or desmin and result in cell death and dysfunction.[26]

Clinical significance

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Mutations in this gene are the cause of several cardiomyopathies, including dilated cardiomyopathy[27][28] and arrhythmogenic right ventricular cardiomyopathy.[25][29][30][31][32][17] The presence of pathogenic mutations in this gene has been associated with episodes of acute myocardial injury, which may mimic episodes of myocarditis.[33][34] Mutations in DSP have also been associated with striate palmoplantar keratoderma.[27][31][35][36][37] Carvajal syndrome results from an autosomal recessive mutation of a frameshift (7901delG) in DSP that results in a combination of above conditions, including dilated cardiomyopathy, keratoderma and woolly hair.[38] Patients with Carvajal syndrome often suffer from heart failure in teenage years. A case of compound heterozygosity for two DSP nonsense mutations resulting in lethal acantholytic epidermolysis bullosa has been reported.[39][40] Autoantibodies to DSP are a hallmark of the autoimmune disease paraneoplastic pemphigus.[41][42] Decreased desmoplakin expression has been found in patients with oropharyngeal cancer and breast cancer, which may alter cell-cell adhesion properties and propagate metastasis.[43][44]

Interactions

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Desmoplakin has been shown to interact with:

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000096696Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000054889Ensembl, 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, Wheeler GN, Parker AE, Buxton RS (October 1991). "Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP)". Genomics. 10 (3): 640–5. doi:10.1016/0888-7543(91)90446-L. PMID 1889810.
  6. ^ "Entrez Gene: DSP desmoplakin".
  7. ^ Bornslaeger EA, Corcoran CM, Stappenbeck TS, Green KJ (August 1996). "Breaking the connection: displacement of the desmosomal plaque protein desmoplakin from cell-cell interfaces disrupts anchorage of intermediate filament bundles and alters intercellular junction assembly". J. Cell Biol. 134 (4): 985–1001. doi:10.1083/jcb.134.4.985. PMC 2120955. PMID 8769422.
  8. ^ Schoonvelde SA, Hirsch A, Yap SC (2022). "Desmoplakin cardiomyopathy—an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury". Neth Heart J. 31 (7–8): 282–286. doi:10.1007/s12471-022-01735-2. PMC 10400739. PMID 36434384.
  9. ^ Scheel PJ, Murray B, Tichnell C (2021). "Arrhythmogenic right ventricular cardiomyopathy presenting as clinical myocarditis in women". Am J Cardiol. 145: 128–134. doi:10.1016/j.amjcard.2020.12.090. PMID 33460606. S2CID 231641047.
  10. ^ "Protein sequence of human desmoplakin (Uniprot ID: P15924)". Cardiac Organellar Protein Atlas Knowledgabase (COPaKB). Archived from the original on 27 June 2015. Retrieved 26 June 2015.
  11. ^ "Protein sequence of human desmoplakin (Uniprot ID: P15924-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 27 June 2015. Retrieved 26 June 2015.
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  27. ^ a b Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP (Nov 2000). "Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma". Human Molecular Genetics. 9 (18): 2761–6. doi:10.1093/hmg/9.18.2761. PMID 11063735.
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  34. ^ Scheel PJ, Murray B, Tichnell C (2021). "Arrhythmogenic right ventricular cardiomyopathy presenting as clinical myocarditis in women". Am J Cardiol. 145: 128–134. doi:10.1016/j.amjcard.2020.12.090. PMID 33460606. S2CID 231641047.
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Further reading

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