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Mutations in the catalytic domain of human β-cardiac myosin that cause early onset hypertrophic cardiomyopathy significantly increase the fundamental parameters that determine ensemble force and velocity

Arjun S. Adhikari, Kristina B. Kooiker, Chao Liu, Saswata S. Sarkar, Daniel Bernstein, James A. Spudich, Kathleen M. Ruppel
doi: https://doi.org/10.1101/067066
Arjun S. Adhikari
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305
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Kristina B. Kooiker
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305
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Chao Liu
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305
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Saswata S. Sarkar
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305
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Daniel Bernstein
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305
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James A. Spudich
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305
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  • For correspondence: jspudich@stanford.edu kruppel@stanford.edu
Kathleen M. Ruppel
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305
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  • For correspondence: jspudich@stanford.edu kruppel@stanford.edu
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Abstract

Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. In infants it can be particularly severe and it is the leading cause of sudden cardiac death in pediatric populations. A high percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two mutations that cause early-onset HCM, D239N and H251N, affect the mechanical output of human β-cardiac myosin at the molecular level. We observe extremely large increases (25% – 95%) in the actin gliding velocity, single molecule intrinsic force, and ATPase activity of the two mutant myosin motors compared to wild type myosin. In contrast to previous studies of HCM-causing mutations in human β-cardiac myosin, these mutations were striking in that they caused changes in biomechanical parameters that were both greater in magnitude and more uniformly consistent with a hyper-contractile phenotype. In addition, S1-S2 binding studies revealed a significant decrease in affinity of the H251N motor for S2, suggesting that this mutation may further increase hyper-contractility by releasing active motors from a sequestered state. This report shows, for the first time, a clear and significant gain in function for all tested molecular biomechanical parameters due to HCM mutations in human β-cardiac myosin.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 09, 2016.
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Mutations in the catalytic domain of human β-cardiac myosin that cause early onset hypertrophic cardiomyopathy significantly increase the fundamental parameters that determine ensemble force and velocity
Arjun S. Adhikari, Kristina B. Kooiker, Chao Liu, Saswata S. Sarkar, Daniel Bernstein, James A. Spudich, Kathleen M. Ruppel
bioRxiv 067066; doi: https://doi.org/10.1101/067066
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Mutations in the catalytic domain of human β-cardiac myosin that cause early onset hypertrophic cardiomyopathy significantly increase the fundamental parameters that determine ensemble force and velocity
Arjun S. Adhikari, Kristina B. Kooiker, Chao Liu, Saswata S. Sarkar, Daniel Bernstein, James A. Spudich, Kathleen M. Ruppel
bioRxiv 067066; doi: https://doi.org/10.1101/067066

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