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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Viswanathan MC,Schmidt W,Franz P,Rynkiewicz MJ,Newhard CS,Madan A,Lehman W,Swank DM,Preller M,Cammarato Adoi
10.1038/s41467-020-15922-5subject
Has Abstractpub_date
2020-05-15 00:00:00pages
2417issue
1issn
2041-1723pii
10.1038/s41467-020-15922-5journal_volume
11pub_type
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