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Article Dans Une Revue Nature Communications Année : 2023

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

Alessandro Grinzato
  • Fonction : Auteur
Daniel Auguin
Carlos Kikuti
Neha Nandwani
Dihia Moussaoui
  • Fonction : Auteur
Divya Pathak
  • Fonction : Auteur
Eaazhisai Kandiah
Kathleen Ruppel
James Spudich

Résumé

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.
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Dates et versions

hal-04267665 , version 1 (23-11-2023)

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Alessandro Grinzato, Daniel Auguin, Carlos Kikuti, Neha Nandwani, Dihia Moussaoui, et al.. Cryo-EM structure of the folded-back state of human β-cardiac myosin. Nature Communications, 2023, 14 (1), pp.3166. ⟨10.1038/s41467-023-38698-w⟩. ⟨hal-04267665⟩
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