Biology:Plakophilin-2

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Short description: Protein-coding gene in the species Homo sapiens


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

Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene.[1][2] Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.

Structure

Two splice variants of the PKP2 gene have been identified. The first has a molecular weight of 97.4 kDa (881 amino acids) and the second of molecular weight of 92.7 kDa (837 amino acids).[3][4] A processed pseudogene with high similarity to this locus has been mapped to chromosome 12p13.[2]

Plakophilin-2 is a member of the armadillo repeat and plakophilin protein family. Plakophilin proteins contain nine central, conserved armadillo repeat domains flanked by N-terminal and C-terminal domains.[5] Alternately spliced transcripts encoding protein isoforms have been identified.[6]

Plakophilin 2 localizes to cell desmosomes and nuclei and binds plakoglobin, desmoplakin, and the desmosomal cadherins via N-terminal head domain.[7][8]

Function

Plakophilin 2 functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiomyocytes, plakophilin-2 is found at desmosome structures within intercalated discs, which link adjacent sarcolemmal membranes together.[9] The desmosomal protein, desmoplakin, is the core constituent of the plaque which anchors intermediate filaments to the sarcolemma by its C-terminus and indirectly to sarcolemmal cadherins by its N-terminus, facilitated by plakoglobin and plakophilin-2.[10] Plakophilin is necessary for normal localization and content of desmoplakin to desmosomes, which may in part be due to the recruitment of protein kinase C alpha to desmoplakin.[11]

Ablation of PKP2 in mice severely disrupts normal heart morphogenesis. Mutant mice are embryonic lethal and exhibit deficits in the formation of adhering junctions in cardiomyocytes, including the dissociation of desmoplakin and formation of cytoplasmic granular aggregates around embryonic day 10.5-11. Additional malformation included reduced trabeculation, cytoskeletal disarray and cardiac wall rupture.[12] Further studies demonstrated that plakophilin-2 coordinate with E-cadherin is required to properly localize RhoA early in actin cytoskeletal rearrangement in order to properly couple the assembly of adherens junctions to the translocation of desmosome precursors in newly formed cell-cell junctions.[13]

Plakophilin-2 over time has shown to be more than components of cell-cell junctions; rather the plakophilins are emerging as versatile scaffolds for various signaling pathways that more globally modulate diverse cellular activities.[5] Plakophilin-2 has shown to localize to nuclei, in addition to desmosomal plaques in the cytoplasm. Studies have shown that plakkophillin-2 is found in the nucleoplasm, complexed in the RNA polymerase III holoenzyme with the largest subunit of RNA polymerase III, termed RPC155.[7]

There are data to support molecular crosstalk between plakophilin-2 and proteins involved in mechanical junctions in cardiomyocytes, including connexin 43, the major component of cardiac gap junctions; the voltage-gated sodium channel Na(V)1.5 and its interacting subunit, ankyrin G; and the K(ATP). Decreased expression of plakophilin-2 via siRNA leads to a decrease in and redistribution of connexin 43 protein, as well as a decrease in coupling of adjacent cardiomyocytes. Studies also showed that GJA1 and plakophilin-2 are components in the same biomolecular complex.[14] Plakophilin-2 also associates with Na(V)1.5, and knockdown of plakophilin-2 in cardiomyocytes alters sodium current properties as well as velocity of action potential propagation.[15] It has also been demonstrated that plakophilin-2 associates with an important component of the Na(V)1.5 complex, ankyrin G, and loss of ankyrin G via siRNA downregulation mislocalized plakophilin-2 and connexin 43 in cardiac cells, which was coordinate with decreased electrical coupling of cells and decreased adhesion strength.[16] These studies were further supported by an investigation in a mouse model harboring a PKP2-heterozygous null mutation, which showed decreased Na(V)1.5 amplitude, as well as a shift in gating and kinetics; pharmacological challenge also induced ventricular arrhythmias. These findings further support the notion that desmosomes crosstalk with sodium channels in the heart, and suggest that the risk of arrhythmias in patients with PKP2 mutations may be unveiled with pharmacological challenge.[17] Evidence has also shown that plakophilin-2 binds to the K(ATP) channel subunit, Kir6.2, and that in cardiomyocytes from haploinsufficient PKP2 mice, K(ATP) channel current density was ~40% smaller and regional heterogeneity of K(ATP) channels was altered, suggesting that plakophilin-2 interacts with K(ATP) and mediates crosstalk between intercellular junctions and membrane excitability.[18]

Clinical significance

Mutations in PKP2 have been associated with, have been shown to cause, and are considered common in arrhythmogenic right ventricular cardiomyopathy, which is characterized by fibrofatty replacement of cardiomyocytes, ventricular tachycardia and sudden cardiac death.[19][20][21][22][23][24][25][26] It is estimated that 70% of all mutations associated with arrhythmogenic right ventricular cardiomyopathy are within the PKP2 gene.[27] These mutations in general appear to disrupt the assembly and stability of desmosomes.[28] Mechanistic studies have shown that certain PKP2 mutations result in instability of the plakophilin-2 protein due to enhanced calpain-mediated degradation.[29]

Specific and sensitive markers of PKP2 and plakoglobin mutation carriers in arrhythmogenic right ventricular cardiomyopathy have been identified to include T-wave inversions, right ventricular wall motion abnormalities, and ventricular extrasystoles.[30] Additionally, immunohistochemical analysis of proteins comprising cardiomyocyte desmosomes has shown to be a highly sensitive and specific diagnostic indicator.[31]

Clinical and genetic characterization of arrhythmogenic right ventricular cardiomyopathy is currently under intense investigation to understand the penetrance associated with PKP2 mutations, as well as other genes encoding desmosomal proteins, in disease progression and outcome.[6][32][33][34][35][36][37][38][39][40][41]

PKP2 mutations were also found to coexist with sodium channelopathies in patients with Brugada syndrome.[42][43]

Additionally, plakophilin-2 was found in adherens junctions of cardiac myxomata tumors analyzed, and absent in patients with noncardiac myxomata, suggesting that plakophilin-2 may serve as a valuable marker in the clinical diagnosis of cardiac myxomata.[44]

Interactions

PKP2 has been shown to interact with:

See also

References

  1. ↑ "Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque". J Cell Biol 135 (4): 1009–25. Jan 1997. doi:10.1083/jcb.135.4.1009. PMID 8922383. 
  2. ↑ 2.0 2.1 "Entrez Gene: PKP2 plakophilin 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5318. 
  3. ↑ "Protein sequence of human PKP2 (Uniprot ID: Q99959)". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q99959. 
  4. ↑ "Protein sequence of human PKP2 (Uniprot ID: Q99959-2)". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q99959-2. 
  5. ↑ 5.0 5.1 "Plakophilins: multifunctional scaffolds for adhesion and signaling". Current Opinion in Cell Biology 21 (5): 708–16. October 2009. doi:10.1016/j.ceb.2009.07.002. PMID 19674883. 
  6. ↑ 6.0 6.1 "Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy". Heart Rhythm 11 (11): 2010–7. November 2014. doi:10.1016/j.hrthm.2014.07.041. PMID 25087486. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 "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. March 2002. doi:10.1074/jbc.M108765200. PMID 11790773. 
  8. ↑ "Nuclear particles containing RNA polymerase III complexes associated with the junctional plaque protein plakophilin 2". Proceedings of the National Academy of Sciences of the United States of America 98 (14): 7795–800. July 2001. doi:10.1073/pnas.141219498. PMID 11416169. Bibcode: 2001PNAS...98.7795M. 
  9. ↑ "Desmosome structure, composition and function". Biochimica et Biophysica Acta (BBA) - Biomembranes 1778 (3): 572–87. March 2008. doi:10.1016/j.bbamem.2007.07.014. PMID 17854763. 
  10. ↑ "Plakins: goliaths that link cell junctions and the cytoskeleton". Nature Reviews Molecular Cell Biology 5 (7): 542–53. July 2004. doi:10.1038/nrm1425. PMID 15232572. 
  11. ↑ "Plakophilin 2: a critical scaffold for PKC alpha that regulates intercellular junction assembly". The Journal of Cell Biology 181 (4): 605–13. May 2008. doi:10.1083/jcb.200712133. PMID 18474624. 
  12. ↑ "Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation". The Journal of Cell Biology 167 (1): 149–60. October 2004. doi:10.1083/jcb.200402096. PMID 15479741. 
  13. ↑ "Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA". Molecular Biology of the Cell 21 (16): 2844–59. August 2010. doi:10.1091/mbc.E10-02-0131. PMID 20554761. 
  14. ↑ "Connexin43 remodeling caused by inhibition of plakophilin-2 expression in cardiac cells". Circulation Research 101 (7): 703–11. September 2007. doi:10.1161/CIRCRESAHA.107.154252. PMID 17673670. 
  15. ↑ 15.0 15.1 "Loss of plakophilin-2 expression leads to decreased sodium current and slower conduction velocity in cultured cardiac myocytes". Circulation Research 105 (6): 523–6. September 2009. doi:10.1161/CIRCRESAHA.109.201418. PMID 19661460. 
  16. ↑ 16.0 16.1 "Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc". Circulation Research 109 (2): 193–201. July 2011. doi:10.1161/CIRCRESAHA.111.247023. PMID 21617128. 
  17. ↑ "Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency". Cardiovascular Research 95 (4): 460–8. September 2012. doi:10.1093/cvr/cvs218. PMID 22764151. 
  18. ↑ 18.0 18.1 "Heterogeneity of ATP-sensitive K+ channels in cardiac myocytes: enrichment at the intercalated disk". The Journal of Biological Chemistry 287 (49): 41258–67. November 2012. doi:10.1074/jbc.M112.412122. PMID 23066018. 
  19. ↑ "Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy". European Journal of Medical Genetics 58 (4): 258–65. April 2015. doi:10.1016/j.ejmg.2015.02.009. PMID 25765472. 
  20. ↑ "Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy". European Journal of Human Genetics 21 (11): 1226–31. November 2013. doi:10.1038/ejhg.2013.39. PMID 23486541. 
  21. ↑ "PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA)". Circulation Journal 76 (1): 189–94. 2012. doi:10.1253/circj.cj-11-0747. PMID 22019812. 
  22. ↑ "Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia". Netherlands Heart Journal 18 (12): 583–91. December 2010. doi:10.1007/s12471-010-0839-5. PMID 21301620. 
  23. ↑ "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy". Nature Genetics 36 (11): 1162–4. November 2004. doi:10.1038/ng1461. PMID 15489853. 
  24. ↑ "Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy". Circulation 113 (3): 356–64. Jan 2006. doi:10.1161/CIRCULATIONAHA.105.561654. PMID 16415378. http://discovery.ucl.ac.uk/8624/1/8624.pdf. 
  25. ↑ "Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: wide spectrum of disease in mutation carriers within a family". Heart Rhythm 3 (8): 939–44. August 2006. doi:10.1016/j.hrthm.2006.04.028. PMID 16876743. 
  26. ↑ "Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy". International Journal of Cardiology 126 (1): 92–100. May 2008. doi:10.1016/j.ijcard.2007.03.137. PMID 17521752. 
  27. ↑ "Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy". Circulation 113 (13): 1650–8. April 2006. doi:10.1161/CIRCULATIONAHA.105.609719. PMID 16567567. 
  28. ↑ "Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability". Cell Communication & Adhesion 16 (1–3): 15–27. 2009. doi:10.1080/15419060903009329. PMID 19533476. 
  29. ↑ "Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations". Circulation: Cardiovascular Genetics 5 (4): 400–11. August 2012. doi:10.1161/CIRCGENETICS.111.961854. PMID 22781308. 
  30. ↑ "Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis". European Heart Journal 27 (18): 2208–16. September 2006. doi:10.1093/eurheartj/ehl184. PMID 16893920. 
  31. ↑ "Cardiomyopathies: New test for arrhythmogenic right ventricular cardiomyopathy". Nature Reviews. Cardiology 6 (7): 450–1. July 2009. doi:10.1038/nrcardio.2009.97. PMID 19554004. 
  32. ↑ "Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study". Circulation 123 (23): 2690–700. June 2011. doi:10.1161/CIRCULATIONAHA.110.988287. PMID 21606396. 
  33. ↑ "Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy". Heart Rhythm 8 (8): 1214–21. August 2011. doi:10.1016/j.hrthm.2011.03.015. PMID 21397041. 
  34. ↑ "Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression". Circulation 115 (13): 1710–20. April 2007. doi:10.1161/CIRCULATIONAHA.106.660241. PMID 17372169. 
  35. ↑ "Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?". Current Opinion in Cardiology 22 (3): 185–92. May 2007. doi:10.1097/HCO.0b013e3280d942c4. PMID 17413274. 
  36. ↑ "Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy". Nature Clinical Practice Cardiovascular Medicine 5 (5): 258–67. May 2008. doi:10.1038/ncpcardio1182. PMID 18382419. 
  37. ↑ "Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy". Circulation: Cardiovascular Genetics 2 (5): 428–35. October 2009. doi:10.1161/CIRCGENETICS.109.858217. PMID 20031617. 
  38. ↑ "Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia". Heart Rhythm 7 (1): 22–9. Jan 2010. doi:10.1016/j.hrthm.2009.09.070. PMID 20129281. 
  39. ↑ "Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice". Europace 12 (6): 861–8. June 2010. doi:10.1093/europace/euq104. PMID 20400443. 
  40. ↑ "Skin-heart connection: what can the epidermis tell us about the myocardium in arrhythmogenic cardiomyopathy?". Circulation: Cardiovascular Genetics 7 (3): 225–7. June 2014. doi:10.1161/CIRCGENETICS.114.000647. PMID 24951656. 
  41. ↑ "Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy". Journal of Medical Genetics 51 (10): 669–76. October 2014. doi:10.1136/jmedgenet-2014-102591. PMID 25157032. 
  42. ↑ "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype". Circulation 129 (10): 1092–103. March 2014. doi:10.1161/CIRCULATIONAHA.113.003077. PMID 24352520. 
  43. ↑ "Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome". Trends in Cardiovascular Medicine 24 (5): 184–90. July 2014. doi:10.1016/j.tcm.2014.02.001. PMID 24656989. 
  44. ↑ "A novel kind of tumor type-characteristic junction: plakophilin-2 as a major protein of adherens junctions in cardiac myxomata". Modern Pathology 23 (11): 1429–37. November 2010. doi:10.1038/modpathol.2010.138. PMID 20693980. 
  45. ↑ "Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque". Cardiovascular Research 100 (2): 231–40. November 2013. doi:10.1093/cvr/cvt191. PMID 23929525. 

Further reading

External links



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