Plakophilin-2

PKP2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3TT9,%%s3TT9
Identifiers
Aliases	PKP2, ARVD9, plakophilin 2
External IDs	OMIM: 602861; MGI: 1914701; HomoloGene: 3364; GeneCards: PKP2; OMA:PKP2 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p11.21 Start 32,790,755 bp[1] End 32,896,777 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 A2 Start 16,031,182 bp[2] End 16,090,576 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right ventricle apex of heart myocardium of left ventricle right uterine tube right auricle cardiac muscle tissue of right atrium mucosa of colon mucosa of sigmoid colon rectum mucosa of transverse colon Top expressed in Ileal epithelium superior surface of tongue gallbladder atrioventricular valve myocardium of ventricle cardiac muscle tissue of left ventricle endocardial cushion atrium Paneth cell epithelium of lens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sodium channel regulator activity intermediate filament binding transmembrane transporter binding protein binding cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication molecular adaptor activity alpha-catenin binding protein kinase C binding cadherin binding Cellular component integral component of membrane intercalated disc cell-cell junction adherens junction plasma membrane desmosome nucleoplasm cell junction intermediate filament nucleus cornified envelope messenger ribonucleoprotein complex cytoplasm Biological process intermediate filament bundle assembly cell communication by electrical coupling involved in cardiac conduction ventricular cardiac muscle cell action potential cardiac muscle cell action potential involved in contraction bundle of His cell-Purkinje myocyte adhesion involved in cell communication cell-cell signaling involved in cardiac conduction ventricular cardiac muscle tissue morphogenesis heart development desmosome assembly cell adhesion positive regulation of sodium ion transport regulation of heart rate by cardiac conduction regulation of ventricular cardiac muscle cell action potential maintenance of animal organ identity keratinization cornification protein localization to plasma membrane cell-cell adhesion cell-cell junction assembly adherens junction maintenance Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 16: 16.03 – 16.09 Mb PubMed search [3] [4]
Wikidata
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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.

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]

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]

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]

PKP2 has been shown to interact with:

• ankyrin G,^[20]
• beta catenin,^[11]
• desmocollin 1,^[11]
• desmocollin 2,^[11]
• desmoglein 1,^[11]
• desmoglein 2,^[11]
• desmoplakin,^[11]
• connexin 43,^[49]
• plakoglobin,^[11]
• Kir6.2,^[22] and
• SCN5A.^[19]

• Skin fragility syndrome

• GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
• OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant