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

Autor:	Viswanathan MC; Department of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA., Schmidt W; Department of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA., Franz P; Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Rynkiewicz MJ; Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street St, Boston, MA, 02118, USA., Newhard CS; Department of Biological Sciences and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180-3590, USA., Madan A; Department of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA., Lehman W; Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street St, Boston, MA, 02118, USA., Swank DM; Department of Biological Sciences and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180-3590, USA., Preller M; Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany. Preller.Matthias@mh-hannover.de., Cammarato A; Department of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA. acammar3@jhmi.edu.; Department of Physiology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA. acammar3@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 May 15; Vol. 11 (1), pp. 2417. Date of Electronic Publication: 2020 May 15.
DOI:	10.1038/s41467-020-15922-5
Abstrakt:	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.
Databáze:	MEDLINE
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