Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.

ABSTRACT: Cardiac TnC (cTnC) is highly conserved among mammals, and genetic variants can result in disease by perturbing Ca²⁺-regulation of myocardial contraction. Here, we report the molecular basis of a human mutation in cTnC's αD-helix (TNNC1-p.C84Y) that impacts conformational dynamics of the D/E central-linker and sampling of discrete states in the N-domain, favoring the "primed" state associated with Ca²⁺ binding. We demonstrate cTnC's αD-helix normally functions as a central hub that controls minimally frustrated interactions, maintaining evolutionarily conserved rigidity of the N-domain. αD-helix perturbation remotely alters conformational dynamics of the N-domain, compromising its structural rigidity. Transgenic mice carrying this cTnC mutation exhibit altered d

SUBMITTER: Marques MA 

PROVIDER: S-EPMC8171346 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature