Contractility parameters of human -cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

Nag, Suman and Sommese, Ruth F. and Ujfalusi, Zoltán and Combs, Ariana and Langer, Stephen and Sutton, Shirley and Leinwand, Leslie A. and Geeves, Michael A. and Ruppel, Kathleen M. and Spudich, James A. (2015) Contractility parameters of human -cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function. Science Advances, 1 (9). e1500511-e1500511. ISSN 2375-2548. (doi:https://doi.org/10.1126/sciadv.1500511) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://doi.org/10.1126/sciadv.1500511

Abstract

Hypertrophic cardiomyopathy (HCM) is the most frequently occurring inherited cardiovascular disease. It is caused by mutations in genes encoding the force-generating machinery of the cardiac sarcomere, including human β-cardiac myosin. We present a detailed characterization of the most debated HCM-causing mutation in human β-cardiac myosin, R403Q. Despite numerous studies, most performed with nonhuman or noncardiac myosin, there is no consensus about the mechanism of action of this mutation on the function of the enzyme. We use recombinant human β-cardiac myosin and new methodologies to characterize in vitro contractility parameters of the R403Q myosin compared to wild type. We extend our studies beyond pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin. We find that, with pure actin, the intrinsic force generated by R403Q is ~15% lower than that generated by wild type. The unloaded velocity is, however, ~10% higher for R403Q myosin, resulting in a load-dependent velocity curve that has the characteristics of lower contractility at higher external loads compared to wild type. With regulated actin filaments, there is no increase in the unloaded velocity and the contractility of the R403Q myosin is lower than that of wild type at all loads. Unlike that with pure actin, the actin-activated adenosine triphosphatase activity for R403Q myosin with Ca2+-regulated actin filaments is ~30% lower than that for wild type, predicting a lower unloaded duty ratio of the motor. Overall, the contractility parameters studied fit with a loss of human β-cardiac myosin contractility as a result of the R403Q mutation.

Item Type: Article
Uncontrolled keywords: High pressure, Crystallography, Metallic alloy, Chemical bonding, electron density, maximum entropy method
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Sue Davies
Date Deposited: 12 Oct 2015 13:24 UTC
Last Modified: 13 Oct 2015 07:59 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/50884 (The current URI for this page, for reference purposes)
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