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

Meera C. Viswanathan, William Schmidt, Peter Franz, Michael J. Rynkiewicz, Christopher S. Newhard, Aditi Madan, William Lehman, Douglas M. Swank, Matthias Preller () and Anthony Cammarato ()
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Meera C. Viswanathan: Johns Hopkins University
William Schmidt: Johns Hopkins University
Peter Franz: Institute for Biophysical Chemistry, Hannover Medical School
Michael J. Rynkiewicz: Boston University School of Medicine
Christopher S. Newhard: Rensselaer Polytechnic Institute
Aditi Madan: Johns Hopkins University
William Lehman: Boston University School of Medicine
Douglas M. Swank: Rensselaer Polytechnic Institute
Matthias Preller: Institute for Biophysical Chemistry, Hannover Medical School
Anthony Cammarato: Johns Hopkins University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Striated 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.

Date: 2020
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DOI: 10.1038/s41467-020-15922-5

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