Myosin with hypertrophic cardiac mutation R712L has a decreased working stroke which is rescued by omecamtiv mecarbil

eLife

Bipasha Barua¹  Donald A Winkelmann¹  Eva Forgacs²  Jennifer L Atherton²  Henry Shuman³  E Michael Ostap³  Yale E Goldman³  Aaron Snoberger³ 

[1] Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, United States;Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, United States;Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States;

关键词: single molecule;    cardiac myosin;    optical trapping;    optical tweezers;    hypertrophic cardiomyopathy;    omecamtiv mecarbil;   

DOI  :  10.7554/eLife.63691

来源: DOAJ

【 摘 要 】

Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

【 授权许可】

Unknown