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

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1464331
Grant/Contract Number:  
[AC02-06CH11357]
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
[Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 35]; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English

Citation Formats

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., and Spudich, James A. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. United States: N. p., 2018. Web. doi:10.1073/pnas.1809540115.
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. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. United States. doi:10.1073/pnas.1809540115.
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., and Spudich, James A. Mon . "Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers". United States. doi:10.1073/pnas.1809540115.
@article{osti_1464331,
title = {Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers},
author = {Anderson, Robert L. and Trivedi, Darshan V. and Sarkar, Saswata S. and Henze, Marcus and Ma, Weikang and Gong, Henry and Rogers, Christopher S. and Gorham, Joshua M. and Wong, Fiona L. and Morck, Makenna M. and Seidman, Jonathan G. and Ruppel, Kathleen M. and Irving, Thomas C. and Cooke, Roger and Green, Eric M. and Spudich, James A.},
abstractNote = {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.},
doi = {10.1073/pnas.1809540115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = [35],
volume = [115],
place = {United States},
year = {2018},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1073/pnas.1809540115

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Cited by: 12 works
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