Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Arjun S. Adhikari, Kristina B. Kooiker, Saswata S. Sarkar, Chao Liu, Daniel Bernstein, James A. Spudich, Kathleen M. Ruppel
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.

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Teaser

Hypertrophic cardiomyopathy (HCM) can be attributed to mutations in β-cardiac myosin. Here, Adhikari et al. show that early-onset HCM mutations, H251N and D239N, significantly increase myosin biomechanical functions. In addition, H251N disrupts S1-S2 intramolecular myosin interactions, potentially releasing more active heads and further contributing to hyper-contractility.


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