A role for actin flexibility in thin filament-mediated contractile regulation and myopathy

Author:

Viswanathan Meera C.,Schmidt William,Franz PeterORCID,Rynkiewicz Michael J.,Newhard Christopher S.,Madan Aditi,Lehman William,Swank Douglas M.,Preller MatthiasORCID,Cammarato Anthony

Abstract

AbstractStriated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.

Funder

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

American Heart Association

Deutsche Forschungsgemeinschaft

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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