Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding.

ABSTRACT: Desmoplakin (DSP) is a large (~260 kDa) protein found in the desmosome, the subcellular structure that links the intermediate filament network of one cell to its neighbor. A mutation "hot-spot" within the NH₂-terminal of the DSP protein (residues 299-515) is associated with arrhythmogenic cardiomyopathy. In a subset of DSP variants, disease is linked to calpain hypersensitivity. Previous studies show that calpain hypersensitivity can be corrected in vitro through the addition of a bulky residue neighboring the cleavage site, suggesting that physically blocking calpain accessibility is a viable strategy to restore DSP levels. Here, we aim to find drug-like molecules that also block calpain-dependent degradation of DSP. To do this, we screened ~2500 small molecules to ident

SUBMITTER: Romov IM 

PROVIDER: S-EPMC10890502 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature