Desmoplakin Explained

Desmoplakin is a protein in humans that is encoded by the DSP gene.^{[1] [2] [3]} 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;^{[4] [5]} striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.

Structure

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).^{[6] [7]} These isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant isoform expressed in cardiac muscle.^[8] The DSP gene is located on chromosome 6p24.3, containing 24 exons and spanning approximately 45 kDa of genomic DNA.^[9] Desmoplakin is a large desmosomal plaque protein that homodimerizes and adopts a dumbbell-shaped conformation.^[9] 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.^[10] This is further sub divided into a region called the "Plakin domain" made up of six spectrin repeat domains separated by SH3 domain.^[11] A crystal structure of part of the plakin domain has been resolved,^[12] 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.^[13] 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] [15]} Located at the most distal C-terminus of desmoplakin is a region rich in glycine–serine–arginine; it has been demonstrated that serine phosphorylation of this domain may modify desmoplakin-intermediate filament interactions.^[16] In the mid-region of desmoplakin, a coiled-coil rod domain is responsible for homodimerization.^[17]

Function

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.^{[17] [18]} Both types of intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque.^[19] 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.^[20] 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.^[21] 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.^[22]

Clinical significance

Mutations in this gene are the cause of several cardiomyopathies, including dilated cardiomyopathy^{[23] [24]} and arrhythmogenic right ventricular cardiomyopathy.^{[21] [25] [26] [27] [28]} The presence of pathogenic mutations in this gene has been associated with episodes of acute myocardial injury, which may mimic episodes of myocarditis.^{[29] [30]} Mutations in DSP have also been associated with striate palmoplantar keratoderma.^{[23] [27] [31] [32] [33]} 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.^[34] 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.^{[35] [36]} Autoantibodies to DSP are a hallmark of the autoimmune disease paraneoplastic pemphigus.^{[37] [38]} Decreased desmoplakin expression has been found in patients with oropharyngeal cancer and breast cancer, which may alter cell-cell adhesion properties and propagate metastasis.^{[39] [40]}

Interactions

Desmoplakin has been shown to interact with:

• Desmin,
• Keratin 1,
• PKP1^[41]
• PKP2,^[42]
• Plakoglobin,^{[43] [44]} and
• Vimentin.^[45]

See also

• List of target antigens in pemphigus
• List of conditions caused by problems with junctional proteins

Further reading

• Presland RB, Dale BA . Epithelial structural proteins of the skin and oral cavity: function in health and disease . Crit. Rev. Oral Biol. Med. . 11 . 4 . 383–408 . 2000 . 11132762 . 10.1177/10454411000110040101 .
• Just M, Herbst H, Hummel M, Dürkop H, Tripier D, Stein H, Schuppan D . Undulin is a novel member of the fibronectin-tenascin family of extracellular matrix glycoproteins . J. Biol. Chem. . 266 . 26 . 17326–32 . 1991 . 10.1016/S0021-9258(19)47377-8 . 1716629 . free .
• Virata ML, Wagner RM, Parry DA, Green KJ . Molecular structure of the human desmoplakin I and II amino terminus . Proc. Natl. Acad. Sci. U.S.A. . 89 . 2 . 544–8 . 1992 . 1731325 . 48275 . 10.1073/pnas.89.2.544 . 1992PNAS...89..544V . free .
• Green KJ, Parry DA, Steinert PM, Virata ML, Wagner RM, Angst BD, Nilles LA . Structure of the human desmoplakins. Implications for function in the desmosomal plaque . J. Biol. Chem. . 265 . 19 . 11406–7 . 1990 . 10.1016/S0021-9258(19)38608-9 . 2391353 . free .
• Kouklis PD, Hutton E, Fuchs E . Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins . J. Cell Biol. . 127 . 4 . 1049–60 . 1994 . 7525601 . 2200061 . 10.1083/jcb.127.4.1049 .
• Steinert PM, Marekov LN . Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope . J. Biol. Chem. . 272 . 3 . 2021–30 . 1997 . 8999895 . 10.1074/jbc.272.3.2021 . free .
• Olavesen MG, Bentley E, Mason RV, Stephens RJ, Ragoussis J . Fine mapping of 39 ESTs on human chromosome 6p23-p25 . Genomics . 46 . 2 . 303–6 . 1997 . 9417921 . 10.1006/geno.1997.5032 .
• Marekov LN, Steinert PM . Ceramides are bound to structural proteins of the human foreskin epidermal cornified cell envelope . J. Biol. Chem. . 273 . 28 . 17763–70 . 1998 . 9651377 . 10.1074/jbc.273.28.17763 . free .
• Suzuki M, Okuyama S, Okamoto S, Shirasuna K, Nakajima T, Hachiya T, Nojima H, Sekiya S, Oda K . A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer . Oncogene . 17 . 7 . 853–65 . 1998 . 9780002 . 10.1038/sj.onc.1202163 . 23588950 .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proc. Natl. Acad. Sci. U.S.A. . 97 . 7 . 3491–6 . 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . free .

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

Notes and References

1. Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS . 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 . October 1991 . 1889810 . 10.1016/0888-7543(91)90446-L .
2. Web site: Entrez Gene: DSP desmoplakin.
3. Bornslaeger EA, Corcoran CM, Stappenbeck TS, Green KJ . 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 . August 1996 . 8769422 . 2120955 . 10.1083/jcb.134.4.985 .
4. Schoonvelde SA, Hirsch A, Yap SC . Desmoplakin cardiomyopathy—an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury . Neth Heart J . 2022 . 31 . 7–8 . 282–286 . 10.1007/s12471-022-01735-2. 36434384 . 10400739 . free .
5. Scheel PJ, Murray B, Tichnell C . Arrhythmogenic right ventricular cardiomyopathy presenting as clinical myocarditis in women. . Am J Cardiol . 2021 . 145 . 128–134 . 10.1016/j.amjcard.2020.12.090. 33460606 . 231641047 .
6. Web site: Protein sequence of human desmoplakin (Uniprot ID: P15924). Cardiac Organellar Protein Atlas Knowledgabase (COPaKB). 26 June 2015. https://web.archive.org/web/20150627034108/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P15924. 27 June 2015. dead.
7. Web site: Protein sequence of human desmoplakin (Uniprot ID: P15924-2). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 26 June 2015. https://web.archive.org/web/20150627022313/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P15924-2. 27 June 2015. dead.
8. Al-Jassar C, Bikker H, Overduin M, Chidgey M . Mechanistic basis of desmosome-targeted diseases . Journal of Molecular Biology . 425 . 21 . 4006–22 . Nov 2013 . 23911551 . 10.1016/j.jmb.2013.07.035 . 3807649.
9. Green KJ, Parry DA, Steinert PM, Virata ML, Wagner RM, Angst BD, Nilles LA . Structure of the human desmoplakins. Implications for function in the desmosomal plaque . The Journal of Biological Chemistry . 265 . 5 . 2603–12 . Feb 1990 . 10.1016/S0021-9258(19)39844-8 . 1689290 . free .
10. Smith EA, Fuchs E . Defining the interactions between intermediate filaments and desmosomes . J. Cell Biol. . 141 . 5 . 1229–41 . 1998 . 9606214 . 2137181 . 10.1083/jcb.141.5.1229 .
11. Jefferson JJ, Ciatto C, Shapiro L, Liem RK . Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily . Journal of Molecular Biology . 366 . 1 . 244–57 . Feb 2007 . 17161423 . 10.1016/j.jmb.2006.11.036 . 1850962.
12. Choi HJ, Weis WI . Crystal structure of a rigid four-spectrin-repeat fragment of the human desmoplakin plakin domain . J. Mol. Biol. . 409 . 5 . 800–12 . 2011 . 21536047 . 3107870 . 10.1016/j.jmb.2011.04.046 .
13. Al-Jassar C, Knowles T, Jeeves M, Kami K, Behr E, Bikker H, Overduin M, Chidgey M . The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations . J. Mol. Biol. . 411 . 5 . 1049–61 . 2011 . 21756917 . 10.1016/j.jmb.2011.06.047 .
14. Choi HJ, Park-Snyder S, Pascoe LT, Green KJ, Weis WI . Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure . Nature Structural Biology . 9 . 8 . 612–20 . Aug 2002 . 12101406 . 10.1038/nsb818 . 10611026 .
15. Stappenbeck TS, Bornslaeger EA, Corcoran CM, Luu HH, Virata ML, Green KJ . Functional analysis of desmoplakin domains: specification of the interaction with keratin versus vimentin intermediate filament networks . The Journal of Cell Biology . 123 . 3 . 691–705 . Nov 1993 . 7693716 . 10.1083/jcb.123.3.691 . 2200123.
16. Stappenbeck TS, Lamb JA, Corcoran CM, Green KJ . Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks . The Journal of Biological Chemistry . 269 . 47 . 29351–4 . Nov 1994 . 10.1016/S0021-9258(18)43881-1 . 7525582 . free .
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20. Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L, Fuchs E . Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage . The Journal of Cell Biology . 143 . 7 . 2009–22 . Dec 1998 . 9864371 . 10.1083/jcb.143.7.2009 . 2175222.
21. Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S, Nadvoretskiy VV, DeFreitas G, Carabello B, Brandon LI, Godsel LM, Green KJ, Saffitz JE, Li H, Danieli GA, Calkins H, Marcus F, Towbin JA . Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy . Circulation Research . 99 . 6 . 646–55 . Sep 2006 . 16917092 . 10.1161/01.RES.0000241482.19382.c6 . free .
22. Awad MM, Calkins H, Judge DP . Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy . Nature Clinical Practice Cardiovascular Medicine . 5 . 5 . 258–67 . May 2008 . 18382419 . 10.1038/ncpcardio1182 . 2822988.
23. Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP . Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma . Human Molecular Genetics . 9 . 18 . 2761–6 . Nov 2000 . 11063735 . 10.1093/hmg/9.18.2761. free .
24. Carvajal-Huerta L . Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy . Journal of the American Academy of Dermatology . 39 . 3 . 418–21 . Sep 1998 . 9738775 . 10.1016/s0190-9622(98)70317-2.
25. Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA . Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy . American Journal of Human Genetics . 71 . 5 . 1200–6 . Nov 2002 . 12373648 . 10.1086/344208 . 385098.
26. Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T . A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair . Journal of the American College of Cardiology . 42 . 2 . 319–27 . Jul 2003 . 12875771 . 10.1016/s0735-1097(03)00628-4. free .
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28. van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, Hofstra RM, van Tintelen JP . A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy . Human Mutation . 30 . 9 . 1278–83 . Sep 2009 . 19569224 . 10.1002/humu.21064 . 7138963 . free .
29. Schoonvelde SA, Hirsch A, Yap SC . Desmoplakin cardiomyopathy—an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury . Neth Heart J . 2022 . 31 . 7–8 . 282–286 . 10.1007/s12471-022-01735-2. 36434384 . 10400739 . free .
30. Scheel PJ, Murray B, Tichnell C . Arrhythmogenic right ventricular cardiomyopathy presenting as clinical myocarditis in women. . Am J Cardiol . 2021 . 145 . 128–134 . 10.1016/j.amjcard.2020.12.090. 33460606 . 231641047 .
31. Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM, Hughes AE . Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma . Human Molecular Genetics . 8 . 1 . 143–8 . Jan 1999 . 9887343 . 10.1093/hmg/8.1.143. free .
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34. Carvajal-Huerta L . Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy . Journal of the American Academy of Dermatology . 39 . 3 . 418–21 . Sep 1998 . 9738775 . 10.1016/s0190-9622(98)70317-2.
35. Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A, Pas HH . Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa . American Journal of Human Genetics . 77 . 4 . 653–60 . Oct 2005 . 16175511 . 10.1086/496901 . 1275614.
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45. Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W . Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments . J. Biol. Chem. . 272 . 34 . 21495–503 . August 1997 . 9261168 . 10.1074/jbc.272.34.21495. free .