Early-onset HCM mutations D239N and H251N significantly increased actin gliding velocity, intrinsic force, and ATPase activity by 20%-90% compared to wild-type human β-cardiac myosin.
Early-onset HCM mutations D239N and H251N lead to significant hyper-contractility by increasing fundamental biomechanical parameters of human β-cardiac myosin.
Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human β-cardiac myosin. We observed significant increases (20%-90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper-contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human β-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility.
Adhikari et al. (Thu,) conducted a other in Hypertrophic cardiomyopathy (HCM). Early-onset HCM mutations D239N and H251N vs. Wild-type myosin was evaluated on Actin gliding velocity, intrinsic force, and ATPase activity. Early-onset HCM mutations D239N and H251N significantly increased actin gliding velocity, intrinsic force, and ATPase activity by 20%-90% compared to wild-type human β-cardiac myosin.