Stabilizing mutations in human desmoplakin with small molecules

Abstract

Desmoplakin (DSP) is an integral component of the desmosome, a subcellular structure that links the intermediate filament networks of adjacent myocytes. In cardiomyocytes, the desmosome maintains both cell-to-cell adhesion and promotes electrical synchronization. Four DSP mutations; R451G, S299R, S507F, and S442F, are strongly correlated with arrhythmogenic cardiomyopathy (ACM) in humans. Analysis of these mutations revealed the exposure of a previously-occluded calpain cleavage site, thus making DSP hypersensitive to calpain degradation.