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

Abstract:

: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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Adhikari AS,Kooiker KB,Sarkar SS,Liu C,Bernstein D,Spudich JA,Ruppel KM

doi

10.1016/j.celrep.2016.11.040

subject

Has Abstract

pub_date

2016-12-13 00:00:00

pages

2857-2864

issue

11

issn

2211-1247

pii

S2211-1247(16)31598-4

journal_volume

17

pub_type

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