Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation.

ABSTRACT: Limb-girdle muscular dystrophy type 2a arises from mutations in the Ca²⁺-activated intracellular cysteine protease calpain-3. This calpain isoform is abundant in skeletal muscle and differs from the main isoforms, calpain-1 and -2, in being a homodimer and having two short insertion sequences. The first of these, IS1, interrupts the protease core and must be cleaved for activation and substrate binding. Here, to learn how calpain-3 can be regulated and inhibited, we determined the structures of the calpain-3 protease core with IS1 present or proteolytically excised. To prevent intramolecular IS1 autoproteolysis, we converted the active-site Cys to Ala. Small-angle X-ray scattering (SAXS) analysis of the C129A mutant suggested that IS1 is disordered and mobile enough to occupy se

SUBMITTER: Ye Q 

PROVIDER: S-EPMC5857979 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature