Fig. 4.

Plakophilin 2 structure and locations of ARVC mutations. A sequence homology-based model of the entire PKP2 arm domain is shown based on a fragment of the PKP2 arm domain (PDB code: 3TT9) [114] and the PKP1 arm repeat domain (PDB code 1XM9) [109] as calculated by the PHYRE server [115]. Point mutations that are known to be pathogenic are shown as either copper (buried) or green (surface exposed). PKP2 exhibits the most numerous and diverse pathogenic mutations found in any desmosomal protein. This includes a mutation “hotspot” involving residues N613 and S615 as well as the newly identified L611R and L614P mutations that are linked to ARVC and are clustered within the hydrophobic core of the PKP2 arm domain.