β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity

Arjun S. Adhikari, Darshan V. Trivedi, Saswata S. Sarkar, Dan Song, Kristina B. Kooiker, Daniel Bernstein, James A. Spudich () and Kathleen M. Ruppel ()
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Arjun S. Adhikari: Stanford University School of Medicine
Darshan V. Trivedi: Stanford University School of Medicine
Saswata S. Sarkar: Stanford University School of Medicine
Dan Song: Stanford University School of Medicine
Kristina B. Kooiker: Stanford University School of Medicine
Daniel Bernstein: Stanford Cardiovascular Institute
James A. Spudich: Stanford University School of Medicine
Kathleen M. Ruppel: Stanford University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10555-9

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