Cryo-EM structure of the folded-back state of human β-cardiac myosin.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 05 2023
31 05 2023
Historique:
received:
02
08
2022
accepted:
11
05
2023
medline:
2
6
2023
pubmed:
1
6
2023
entrez:
31
5
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37258552
doi: 10.1038/s41467-023-38698-w
pii: 10.1038/s41467-023-38698-w
pmc: PMC10232470
doi:
Substances chimiques
Cardiac Myosins
EC 3.6.1.-
Ventricular Myosins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3166Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM033289
Pays : United States
Organisme : NIGMS NIH HHS
ID : RM1 GM131981
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
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