Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.

Autor:	Anderson RL; MyoKardia Inc., South San Francisco, CA 94080., Trivedi DV; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Sarkar SS; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Henze M; MyoKardia Inc., South San Francisco, CA 94080., Ma W; BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616., Gong H; BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616., Rogers CS; Exemplar Genetics, Sioux Center, IA 51250., Gorham JM; Department of Genetics, Harvard Medical School, Boston, MA 02115., Wong FL; MyoKardia Inc., South San Francisco, CA 94080., Morck MM; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305., Seidman JG; Department of Genetics, Harvard Medical School, Boston, MA 02115., Ruppel KM; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305., Irving TC; BioCAT, Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616., Cooke R; Department of Biochemistry, University of California, San Francisco, CA 94158., Green EM; MyoKardia Inc., South San Francisco, CA 94080; egreen@myokardia.com jspudich@stanford.edu., Spudich JA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; egreen@myokardia.com jspudich@stanford.edu.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Aug 28; Vol. 115 (35), pp. E8143-E8152. Date of Electronic Publication: 2018 Aug 13.
DOI:	10.1073/pnas.1809540115
Abstrakt:	Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies. Competing Interests: Conflict of interest statement: J.A.S. is a cofounder of MyoKardia, a biotechnology company developing small molecules that target the sarcomere for the treatment of inherited cardiomyopathies, and of Cytokinetics and is a member of their scientific advisory boards. J.G.S. is a cofounder of MyoKardia and a member of its scientific advisory board. K.M.R. and R.C. are members of the MyoKardia scientific advisory board. R.L.A., M.H., and F.L.W. are employees of and own shares in MyoKardia. E.M.G. owns shares in MyoKardia.
Databáze:	MEDLINE
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