Four hypertrophic cardiomyopathy mutations (R249Q, H251N, D382Y, R719W) significantly increased the fraction of myosin heads functionally accessible for interaction with actin compared to wild-type.
HCM-causing mutations in β-cardiac myosin disrupt intramolecular interactions that normally sequester myosin heads, leading to increased functionally accessible heads and hypercontractility at the molecular level.
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin. Previous studies looking at the effect of HCM mutations on the force, velocity and ATPase activity of the catalytic domain of human β-cardiac myosin have not shown clear trends leading to hypercontractility at the molecular scale. Here we present functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H251N) and head-head (D382Y, R719W) interfaces of a folded-back sequestered state referred to as the interacting heads motif (IHM) lead to a significant increase in the number of heads functionally accessible for interaction with actin. These results provide evidence that HCM mutations can modulate myosin activity by disrupting intramolecular interactions within the proposed sequestered state, which could lead to hypercontractility at the molecular level.
Adhikari et al. (Tue,) conducted a other in Hypertrophic cardiomyopathy. HCM mutations (R249Q, H251N, D382Y, R719W) vs. Wild-type (WT) human β-cardiac myosin was evaluated on Fraction of myosin heads showing fast-phase kinetics (accessible for actin interaction). Four hypertrophic cardiomyopathy mutations (R249Q, H251N, D382Y, R719W) significantly increased the fraction of myosin heads functionally accessible for interaction with actin compared to wild-type.
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