The MYBPC3 D389V mutation caused marked reductions in melting temperatures and altered stiffness and conformer dynamics of the C2 domain compared to wild-type constructs.
The D389V mutation in MYBPC3 causes thermodynamic and mechanical destabilization of the C2 domain, suggesting a pathomechanism for hypertrophic cardiomyopathy involving toxic buildup of misfolded protein and C-zone haploinsufficiency.
Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of MYBPC3, which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with MYBPC3Δ25bp alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in MYBPC3Δ25bp/D389V carriers. Residue D389 lies in the IgI-like C2 domain that is part of the N-terminal region of MyBPC. To probe the effects of mutation D389V on structure, thermostability, and protein–protein interactions, we produced and characterized wild-type and mutant constructs corresponding to the isolated 10 kDa C2 domain and a 52 kDa N-terminal fragment that includes subdomains C0 to C2. Our results show marked reductions in the melting temperatures of D389V mutant constructs. Interactions of construct C0–C2 D389V with the cardiac isoforms of myosin-2 and actin remain unchanged. Molecular dynamics simulations reveal changes in the stiffness and conformer dynamics of domain C2 caused by mutation D389V. Our results suggest a pathomechanism for the development of HCM based on the toxic buildup of misfolded protein in young MYBPC3Δ25bp/D389V carriers that is supplanted and enhanced by C-zone haploinsufficiency at older ages.
Schwäbe et al. (Thu,) conducted a other in Hypertrophic cardiomyopathy. MYBPC3 D389V mutant constructs vs. Wild-type constructs was evaluated on Structure, thermostability, and protein-protein interactions. The MYBPC3 D389V mutation caused marked reductions in melting temperatures and altered stiffness and conformer dynamics of the C2 domain compared to wild-type constructs.