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Plakophilin-2

"PKP2" redirects here. For the 2015 Indian film, see Pyaar Ka Punchnama 2.

Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene.[5][6] 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.

PKP2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPKP2, ARVD9, plakophilin 2
External IDsOMIM: 602861; MGI: 1914701; HomoloGene: 3364; GeneCards: PKP2; OMA:PKP2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5318

67451

Ensembl

ENSG00000057294

ENSMUSG00000041957

UniProt

Q99959

Q9CQ73

RefSeq (mRNA)

NM_004572
NM_001005242

NM_026163

RefSeq (protein)

NP_001005242
NP_004563

NP_080439

Location (UCSC)Chr 12: 32.79 – 32.9 MbChr 16: 16.03 – 16.09 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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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).[7][8] A processed pseudogene with high similarity to this locus has been mapped to chromosome 12p13.[6]

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.[9] Alternately spliced transcripts encoding protein isoforms have been identified.[10]

Plakophilin 2 localizes to cell desmosomes and nuclei and binds plakoglobin, desmoplakin, and the desmosomal cadherins via N-terminal head domain.[11][12]

Function

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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.[13] 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.[14] 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.[15]

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.[16] 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.[17]

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.[9] 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.[11]

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.[18] 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.[19] 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.[20] 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.[21] 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.[22]

Clinical significance

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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.[23][24][25][26][27][28][29][30] It is estimated that 70% of all mutations associated with arrhythmogenic right ventricular cardiomyopathy are within the PKP2 gene.[31] These mutations in general appear to disrupt the assembly and stability of desmosomes.[32] Mechanistic studies have shown that certain PKP2 mutations result in instability of the plakophilin-2 protein due to enhanced calpain-mediated degradation.[33]

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.[34] Additionally, immunohistochemical analysis of proteins comprising cardiomyocyte desmosomes has shown to be a highly sensitive and specific diagnostic indicator.[35]

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.[10][36][37][38][39][40][41][42][43][44][45]

PKP2 mutations were also found to coexist with sodium channelopathies in patients with Brugada syndrome.[46][47]

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.[48]

Interactions

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PKP2 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: ENSG00000057294 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041957 – 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. ^ Mertens C, Kuhn C, Franke WW (January 1997). "Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque". J Cell Biol. 135 (4): 1009–25. doi:10.1083/jcb.135.4.1009. PMC 2133394. PMID 8922383.
  6. ^ a b "Entrez Gene: PKP2 plakophilin 2".
  7. ^ "Protein sequence of human PKP2 (Uniprot ID: Q99959)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 12 July 2015. Retrieved 11 July 2015.
  8. ^ "Protein sequence of human PKP2 (Uniprot ID: Q99959-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 12 July 2015. Retrieved 11 July 2015.
  9. ^ a b Bass-Zubek AE, Godsel LM, Delmar M, Green KJ (October 2009). "Plakophilins: multifunctional scaffolds for adhesion and signaling". Current Opinion in Cell Biology. 21 (5): 708–16. doi:10.1016/j.ceb.2009.07.002. PMC 3091506. PMID 19674883.
  10. ^ a b Groeneweg JA, Ummels A, Mulder M, Bikker H, van der Smagt JJ, van Mil AM, Homfray T, Post JG, Elvan A, van der Heijden JF, Houweling AC, Jongbloed JD, Wilde AA, van Tintelen JP, Hauer RN, Dooijes D (November 2014). "Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy". Heart Rhythm. 11 (11): 2010–7. doi:10.1016/j.hrthm.2014.07.041. PMID 25087486.
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Further reading

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