PKP2

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

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

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

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

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

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 is_associated_with::cardiomyocytes, including the dissociation of desmoplakin and formation of cytoplasmic granular aggregates around embryonic day 10.5-11. Additional malformation included reduced trabeculation, cytoskeletal dissaray and cardiac wall rupture. Further studies demonstrated that plakophilin-2 coordinate with is_associated_with::E-cadherin is required to properly localize is_associated_with::RhoA early in is_associated_with::actin cytoskeletal rearrangement in order to properly couple the assembly of is_associated_with::adherens junctions to the translocation of is_associated_with::desmosome precursors in newly formed cell-cell junctions.

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. Plakophilin-2 has shown to localize to nuclei, in addition to desmosomal plaques in the is_associated_with::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.

There are data to support molecular crosstalk between plakophilin-2 and proteins involved in mechanical junctions in is_associated_with::cardiomyocytes, including connexin 43, the major component of cardiac is_associated_with::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 is_associated_with::siRNA leads to a decrease in and redistribution of connexin 43 is_associated_with::protein, as well as a decrease in coupling of adjacent is_associated_with::cardiomyocytes. Studies also showed that is_associated_with::GJA1 and plakophilin-2 are components in the same is_associated_with::biomolecular complex. Plakophilin-2 also associates with Na(V)1.5, and knockdown of plakophilin-2 in is_associated_with::cardiomyocytes alters sodium current properties as well as velocity of is_associated_with::action potential propagation. 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 is_associated_with::siRNA downregulation mislocalized plakophilin-2 and connexin 43 in cardiac cells, which was coordinate with decreased electrical coupling of cells and decreased adhesion strength. These studies were further supported by an investigation in a mouse model harboring a PKP2-is_associated_with::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 is_associated_with::arrhythmias. These findings further support the notion that is_associated_with::desmosomes crosstalk with sodium channels in the heart, and suggest that the risk of is_associated_with::arrhythmias in patients with PKP2 mutations may be unveiled with pharmacological challenge. Evidence has also shown that plakophilin-2 binds to the K(ATP) channel subunit, Kir6.2, and that in is_associated_with::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.

Clinical Significance
Mutations in PKP2 have been associated with, have shown to causal in, and are considered common in is_associated_with::arrhythmogenic right ventricular cardiomyopathy, which is characterized by fibrofatty replacement of is_associated_with::cardiomyocytes, ventricular is_associated_with::tachycardia and is_associated_with::sudden cardiac death. It is estimated that 70% of all mutations associated with is_associated_with::arrhythmogenic right ventricular cardiomyopathy are within the PKP2 is_associated_with::gene. These mutations in general appear to disrupt the assembly and stability of is_associated_with::desmosomes. Mechanistic studies have shown that certain PKP2 mutations result in instability of the plakophilin-2 protein due to enhanced is_associated_with::calpain-mediated degradation.

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

Clinical and genetic characterization of is_associated_with::arrhythmogenic right ventricular cardiomyopathy is currently under intense investigation to understand the is_associated_with::penetrance associated with PKP2 mutations, as well as other genes encoding desmosomal proteins, in disease progression and outcome.

PKP2 mutations were also found to coexist with sodium chanelopathies in patients with is_associated_with::Brugada syndrome.

Additionally, plakophilin-2 was found in is_associated_with::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.

Interactions
PKP2 has been shown to interact with:
 * ankyrin G,
 * beta catenin,
 * desmocollin 1,
 * desmocollin 2,
 * desmoglein 1,
 * desmoglein 2,
 * desmoplakin,
 * connexin 43,
 * plakoglobin,
 * Kir6.2, and
 * is_associated_with::SCN5A.