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

Alessandro Grinzato, Daniel Auguin, Carlos Kikuti, Neha Nandwani, Dihia Moussaoui, Divya Pathak, Eaazhisai Kandiah, Kathleen M. Ruppel (), James A. Spudich, Anne Houdusse () and Julien Robert-Paganin ()
Additional contact information
Alessandro Grinzato: CM01 beamline. European Synchrotron Radiation Facility (ESRF)
Daniel Auguin: Sorbonne Université
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
James A. Spudich: Stanford University School of Medicine
Anne Houdusse: Sorbonne Université
Julien Robert-Paganin: Sorbonne Université

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38698-w

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