A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment.

Hypertrophic cardiomyopathy (HCM) is a leading cause of cardiac failure among individuals under 35. Many genetic mutations that cause HCM enhance ventricular systolic function, suggesting that these HCM mutations are hypercontractile. Among the most common causes of HCM are mutations in the gene MYH7, which encodes for β-cardiac myosin, the principal human ventricular myosin. Previous work has demonstrated that, for purified myosins, some MYH7 mutations are gain-of-function while others cause reduced function, so how they lead to enhanced contractility is not clear. Here, we have characterized the mechanics and kinetics of the severe HCM-causing mutation M493I. Motility assays demonstrate a 70% reduction of actin filament gliding velocities on M493I-coated surfaces relative to WT. This mutation slows ADP release from actomyosin·ADP 5-fold without affecting phosphate release or ATP binding. Yet it enhances steady-state ATPase Significance Statement: Hypertrophic cardiomyopathy (HCM) is a leading genetic cause of sudden cardiac death in young individuals. Although often described as a hypercontractile disease, the molecular basis for this remains unclear, especially for mutations with inhibitory effects in various