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

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 pathol...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 35; pp. E8143 - E8152
Main Authors Anderson, Robert L., Trivedi, Darshan V., Sarkar, Saswata S., Henze, Marcus, Ma, Weikang, Gong, Henry, Rogers, Christopher S., Gorham, Joshua M., Wong, Fiona L., Morck, Makenna M., Seidman, Jonathan G., Ruppel, Kathleen M., Irving, Thomas C., Cooke, Roger, Green, Eric M., Spudich, James A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.08.2018
SeriesPNAS Plus
Subjects
Actin
Adenosine triphosphatase
Animals
BASIC BIOLOGICAL SCIENCES
Benzylamines - chemistry
Benzylamines - pharmacology
Biological Sciences
cardiac inhibitor
Cardiomegaly - enzymology
Cardiomegaly - genetics
Cardiomyocytes
Cardiomyopathy
Contraction
Genetics
Heart
Humans
Hydrology
interacting heads motif
mavacamten
Mode of action
Muscle contraction
Muscle, Skeletal - enzymology
Muscles
Mutation
Myosin
PNAS Plus
Proteins
super relaxed state
Swine
Swine, Miniature
Uracil - analogs & derivatives
Uracil - chemistry
Uracil - pharmacology
Ventricular Myosins - chemistry
Ventricular Myosins - genetics
Ventricular Myosins - metabolism
myosin
interacting heads motif
mavacamten
super relaxed state
cardiac inhibitor
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Summary: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.
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AC02-06CH11357; GM33289; HL117138; AR062279; HL084553; P41 GM103622
National Institutes of Health (NIH)
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
Edited by Thomas D. Pollard, Yale University, New Haven, CT, and approved July 19, 2018 (received for review June 5, 2018)
Author contributions: R.L.A., D.V.T., S.S.S., K.M.R., T.C.I., R.C., E.M.G., and J.A.S. designed research; R.L.A., D.V.T., S.S.S., M.H., W.M., H.G., J.G., F.L.W., M.M.M., K.M.R., R.C., E.M.G., and J.A.S. performed research; R.L.A., D.V.T., S.S.S., M.H., W.M., H.G., C.S.R., J.G., F.L.W., M.M.M., J.G.S., K.M.R., T.C.I., R.C., E.M.G., and J.A.S. contributed new reagents/analytic tools; R.L.A., D.V.T., S.S.S., M.H., W.M., H.G., J.G., F.L.W., M.M.M., J.G.S., K.M.R., T.C.I., R.C., E.M.G., and J.A.S. analyzed data; and R.L.A., D.V.T., S.S.S., K.M.R., T.C.I., R.C., E.M.G., and J.A.S. wrote the paper.
1R.L.A., D.V.T., and S.S.S. contributed equally to this work.
2E.M.G. and J.A.S. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1809540115