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Cryo-EM structure of the folded-back state of human β-cardiac myosin

Author

Listed:
  • Alessandro Grinzato

    (CM01 beamline. European Synchrotron Radiation Facility (ESRF))

  • Daniel Auguin

    (Sorbonne Université
    Université d’Orléans)

  • Carlos Kikuti

    (Sorbonne Université)

  • Neha Nandwani

    (Stanford University School of Medicine)

  • Dihia Moussaoui

    (BM29 BIOSAXS beamline, European Synchrotron Radiation Facility (ESRF))

  • Divya Pathak

    (Stanford University School of Medicine)

  • Eaazhisai Kandiah

    (CM01 beamline. European Synchrotron Radiation Facility (ESRF))

  • Kathleen M. Ruppel

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • James A. Spudich

    (Stanford University School of Medicine)

  • Anne Houdusse

    (Sorbonne Université)

  • Julien Robert-Paganin

    (Sorbonne Université)

Abstract

To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an ‘off’ state that can be converted to an ‘on’ state when exertion is increased. The ‘off’ state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the ‘off’ state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the ‘off’ state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38698-w
    DOI: 10.1038/s41467-023-38698-w
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    References listed on IDEAS

    as
    1. Shixin Yang & Prince Tiwari & Kyoung Hwan Lee & Osamu Sato & Mitsuo Ikebe & Raúl Padrón & Roger Craig, 2020. "Cryo-EM structure of the inhibited (10S) form of myosin II," Nature, Nature, vol. 588(7838), pages 521-525, December.
    2. Vicente J. Planelles-Herrero & James J. Hartman & Julien Robert-Paganin & Fady I. Malik & Anne Houdusse, 2017. "Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    3. Julien Robert-Paganin & Daniel Auguin & Anne Houdusse, 2018. "Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    4. Julien Robert-Paganin & Xiao-Ping Xu & Mark F. Swift & Daniel Auguin & James P. Robblee & Hailong Lu & Patricia M. Fagnant & Elena B. Krementsova & Kathleen M. Trybus & Anne Houdusse & Niels Volkmann , 2021. "The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    5. 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.
    6. Charlotte A. Scarff & Glenn Carrington & David Casas-Mao & Joseph M. Chalovich & Peter J. Knight & Neil A. Ranson & Michelle Peckham, 2020. "Structure of the shutdown state of myosin-2," Nature, Nature, vol. 588(7838), pages 515-520, December.
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    Cited by:

    1. Fengfeng Niu & Lingxuan Li & Lei Wang & Jinman Xiao & Shun Xu & Yong Liu & Leishu Lin & Cong Yu & Zhiyi Wei, 2024. "Autoinhibition and activation of myosin VI revealed by its cryo-EM structure," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Daniel Auguin & Julien Robert-Paganin & Stéphane Réty & Carlos Kikuti & Amandine David & Gabriele Theumer & Arndt W. Schmidt & Hans-Joachim Knölker & Anne Houdusse, 2024. "Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Anthony L. Hessel & Nichlas M. Engels & Michel N. Kuehn & Devin Nissen & Rachel L. Sadler & Weikang Ma & Thomas C. Irving & Wolfgang A. Linke & Samantha P. Harris, 2024. "Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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