Key result
Hypertrophic cardiomyopathy mutations at the myosin head-tail and head-head interfaces significantly increased the number of functionally accessible myosin heads compared to wild-type myosin.
Why the study?
Previous studies evaluating the effect of HCM mutations on the catalytic domain of human beta-cardiac myosin had not shown clear trends leading to hypercontractility at the molecular scale.
Do HCM mutations at the S1-S2 and S1-S1 interfaces of human β-cardiac myosin increase myosin enzymatic activity by releasing sequestered heads?
Do HCM mutations at the S1-S2 and S1-S1 interfaces of human β-cardiac myosin increase myosin enzymatic activity by releasing sequestered heads?
HCM mutations at the myosin head-tail and head-head interfaces disrupt the sequestered interacting heads motif, increasing the number of functionally accessible heads and leading to 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 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, thereby leading to hypercontractility at the molecular level.
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Adhikari et al. (2019) studied Hypertrophic cardiomyopathy (in vitro model). Hypertrophic cardiomyopathy mutations (R249Q, H251N, D382Y, R719W) vs. Wild-type human β-cardiac myosin was evaluated on Fraction of myosin heads in the fast phase (functionally accessible). Hypertrophic cardiomyopathy mutations at the myosin head-tail and head-head interfaces significantly increased the number of functionally accessible myosin heads compared to wild-type myosin.
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