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

• Published in: Nature communications Vol. 11; no. 1; p. 2417
• Main Authors: Viswanathan, Meera C., Schmidt, William, Franz, Peter, Rynkiewicz, Michael J., Newhard, Christopher S., Madan, Aditi, Lehman, William, Swank, Douglas M., Preller, Matthias, Cammarato, Anthony
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 14; 14/19; 631/114; 631/443; 631/45; 631/57; 631/80; 64; 64/24; Actin; Actin Cytoskeleton - metabolism; Actins - chemistry; Actomyosin; Animals; Animals, Genetically Modified; Calcium-binding protein; Cardiac muscle; Cardiomyopathy; Cardiomyopathy, Hypertrophic; Computational Biology; Conformation; Drosophila melanogaster - metabolism; Female; Filaments; Flexibility; Flight, Animal; Humanities and Social Sciences; Humans; Hydrogen Bonding; In vivo methods and tests; Male; Microscopy, Fluorescence; Molecular Dynamics Simulation; multidisciplinary; Muscle Contraction; Muscles; Muscular Diseases - pathology; Muscular function; Mutation; Myopathy; Principal Component Analysis; Properties (attributes); Protein Multimerization; Residues; Science; Science (multidisciplinary); Skeletal muscle; Static Electricity; Transgenes; Translocation; Tropomyosin; Tropomyosin - chemistry; Troponin
• DOI: 10.1038/s41467-020-15922-5
• ISSN: 2041-1723

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. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation is located near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here the authors assessed M305L actin in vivo, in vitro, and in silico to characterize emergent pathological properties and define the mechanistic basis of disease.