Jul 26, 2016

Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy

BioRxiv : the Preprint Server for Biology
Masataka KawanaJames A Spudich

Abstract

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hyper-contractility, and therapies are aimed toward controlling the hyperactive physiology. β-cardiac myosin comprises ~40 percent of genetic mutations associated with HCM and the converter domain of myosin is a hot spot for HCM-causing mutations, but the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations R719W, R723G and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type, and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15 percent faster for R719W and R723G myosin, while there is no change in velocity for G741R. ATPase activities and the load-dependent velocity change profiles of all thr...Continue Reading

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Mentioned in this Paper

Sarcomeres
Ventricular beta-Myosin
Pyotraumatic Dermatitis
Hot Spot
Adenosine Triphosphatases
Actins
Hypertrophic Cardiomyopathy
Hyperactive Behavior
Mutant Proteins
Protein-Protein Interaction

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