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

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...

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Autores principales: Grinzato, Alessandro, Auguin, Daniel, Kikuti, Carlos, Nandwani, Neha, Moussaoui, Dihia, Pathak, Divya, Kandiah, Eaazhisai, Ruppel, Kathleen M., Spudich, James A., Houdusse, Anne, Robert-Paganin, Julien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232470/
https://www.ncbi.nlm.nih.gov/pubmed/37258552
http://dx.doi.org/10.1038/s41467-023-38698-w
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author Grinzato, Alessandro
Auguin, Daniel
Kikuti, Carlos
Nandwani, Neha
Moussaoui, Dihia
Pathak, Divya
Kandiah, Eaazhisai
Ruppel, Kathleen M.
Spudich, James A.
Houdusse, Anne
Robert-Paganin, Julien
author_facet Grinzato, Alessandro
Auguin, Daniel
Kikuti, Carlos
Nandwani, Neha
Moussaoui, Dihia
Pathak, Divya
Kandiah, Eaazhisai
Ruppel, Kathleen M.
Spudich, James A.
Houdusse, Anne
Robert-Paganin, Julien
author_sort Grinzato, Alessandro
collection PubMed
description 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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spelling pubmed-102324702023-06-02 Cryo-EM structure of the folded-back state of human β-cardiac myosin Grinzato, Alessandro Auguin, Daniel Kikuti, Carlos Nandwani, Neha Moussaoui, Dihia Pathak, Divya Kandiah, Eaazhisai Ruppel, Kathleen M. Spudich, James A. Houdusse, Anne Robert-Paganin, Julien Nat Commun Article 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. Nature Publishing Group UK 2023-05-31 /pmc/articles/PMC10232470/ /pubmed/37258552 http://dx.doi.org/10.1038/s41467-023-38698-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Grinzato, Alessandro
Auguin, Daniel
Kikuti, Carlos
Nandwani, Neha
Moussaoui, Dihia
Pathak, Divya
Kandiah, Eaazhisai
Ruppel, Kathleen M.
Spudich, James A.
Houdusse, Anne
Robert-Paganin, Julien
Cryo-EM structure of the folded-back state of human β-cardiac myosin
title Cryo-EM structure of the folded-back state of human β-cardiac myosin
title_full Cryo-EM structure of the folded-back state of human β-cardiac myosin
title_fullStr Cryo-EM structure of the folded-back state of human β-cardiac myosin
title_full_unstemmed Cryo-EM structure of the folded-back state of human β-cardiac myosin
title_short Cryo-EM structure of the folded-back state of human β-cardiac myosin
title_sort cryo-em structure of the folded-back state of human β-cardiac myosin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232470/
https://www.ncbi.nlm.nih.gov/pubmed/37258552
http://dx.doi.org/10.1038/s41467-023-38698-w
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