Myosin with hypertrophic cardiac mutation r712l has a decreased working stroke which is rescued by omecamtiv mecarbil

Aaron Snoberger; Bipasha Barua; Jennifer L. Atherton; Henry Shuman; Eva Forgacs; Yale E. Goldman; Donald A. Winkelmann; E. Michael Ostap

doi:10.7554/eLife.63691

Myosin with hypertrophic cardiac mutation r712l has a decreased working stroke which is rescued by omecamtiv mecarbil

Aaron Snoberger, Bipasha Barua, Jennifer L. Atherton, Henry Shuman, Eva Forgacs, Yale E. Goldman, Donald A. Winkelmann, E. Michael Ostap

Robert Wood Johnson Medical School (RWJMS), Pathology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout b-cardiac myosin, including in the motor domain, are associated with HCM. A b-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal b-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

Original language	American English
Article number	e63691
Pages (from-to)	1-24
Number of pages	24
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.63691
State	Published - Feb 2021

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.63691

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title = "Myosin with hypertrophic cardiac mutation r712l has a decreased working stroke which is rescued by omecamtiv mecarbil",

abstract = "Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout b-cardiac myosin, including in the motor domain, are associated with HCM. A b-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal b-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.",

author = "Aaron Snoberger and Bipasha Barua and Atherton, {Jennifer L.} and Henry Shuman and Eva Forgacs and Goldman, {Yale E.} and Winkelmann, {Donald A.} and Ostap, {E. Michael}",

note = "Publisher Copyright: {\textcopyright} Snoberger et al.",

year = "2021",

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doi = "10.7554/eLife.63691",

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volume = "10",

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AU - Snoberger, Aaron

AU - Barua, Bipasha

AU - Atherton, Jennifer L.

AU - Shuman, Henry

AU - Forgacs, Eva

AU - Goldman, Yale E.

AU - Winkelmann, Donald A.

AU - Ostap, E. Michael

PY - 2021/2

Y1 - 2021/2

N2 - Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout b-cardiac myosin, including in the motor domain, are associated with HCM. A b-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal b-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

AB - Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout b-cardiac myosin, including in the motor domain, are associated with HCM. A b-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal b-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

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Myosin with hypertrophic cardiac mutation r712l has a decreased working stroke which is rescued by omecamtiv mecarbil

Abstract

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