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β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity

Author

Listed:
  • Arjun S. Adhikari

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute)

  • Darshan V. Trivedi

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute)

  • Saswata S. Sarkar

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute)

  • Dan Song

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute)

  • Kristina B. Kooiker

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute
    Stanford University School of Medicine)

  • Daniel Bernstein

    (Stanford Cardiovascular Institute
    Stanford University School of Medicine)

  • James A. Spudich

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute)

  • Kathleen M. Ruppel

    (Stanford University School of Medicine
    Stanford Cardiovascular Institute
    Stanford University School of Medicine)

Abstract

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin. Previous studies looking at the effect of HCM mutations on the force, velocity and ATPase activity of the catalytic domain of human β-cardiac myosin have not shown clear trends leading to hypercontractility at the molecular scale. Here we present functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H251N) and head-head (D382Y, R719W) interfaces of a folded-back sequestered state referred to as the interacting heads motif (IHM) lead to a significant increase in the number of heads functionally accessible for interaction with actin. These results provide evidence that HCM mutations can modulate myosin activity by disrupting intramolecular interactions within the proposed sequestered state, which could lead to hypercontractility at the molecular level.

Suggested Citation

  • Arjun S. Adhikari & Darshan V. Trivedi & Saswata S. Sarkar & Dan Song & Kristina B. Kooiker & Daniel Bernstein & James A. Spudich & Kathleen M. Ruppel, 2019. "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10555-9
    DOI: 10.1038/s41467-019-10555-9
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    Cited by:

    1. Alessandro Grinzato & Daniel Auguin & Carlos Kikuti & Neha Nandwani & Dihia Moussaoui & Divya Pathak & Eaazhisai Kandiah & Kathleen M. Ruppel & James A. Spudich & Anne Houdusse & Julien Robert-Paganin, 2023. "Cryo-EM structure of the folded-back state of human β-cardiac myosin," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Antonia Vogel & Renato Arnese & Ricardo M. Gudino Carrillo & Daria Sehr & Luiza Deszcz & Andrzej Bylicki & Anton Meinhart & Tim Clausen, 2024. "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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