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Structure of the native myosin filament in the relaxed cardiac sarcomere

The thick filament is a key component of sarcomeres, the basic units of striated muscle(1). Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases(2). Despite the central importance of the thick filament, its molecular orga...

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Autores principales: Tamborrini, Davide, Wang, Zhexin, Wagner, Thorsten, Tacke, Sebastian, Stabrin, Markus, Grange, Michael, Kho, Ay Lin, Rees, Martin, Bennett, Pauline, Gautel, Mathias, Raunser, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10665186/
https://www.ncbi.nlm.nih.gov/pubmed/37914933
http://dx.doi.org/10.1038/s41586-023-06690-5
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author Tamborrini, Davide
Wang, Zhexin
Wagner, Thorsten
Tacke, Sebastian
Stabrin, Markus
Grange, Michael
Kho, Ay Lin
Rees, Martin
Bennett, Pauline
Gautel, Mathias
Raunser, Stefan
author_facet Tamborrini, Davide
Wang, Zhexin
Wagner, Thorsten
Tacke, Sebastian
Stabrin, Markus
Grange, Michael
Kho, Ay Lin
Rees, Martin
Bennett, Pauline
Gautel, Mathias
Raunser, Stefan
author_sort Tamborrini, Davide
collection PubMed
description The thick filament is a key component of sarcomeres, the basic units of striated muscle(1). Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases(2). Despite the central importance of the thick filament, its molecular organization remains unclear. Here we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by cryo-electron tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin, titin and myosin-binding protein C (MyBP-C). The arrangement of myosin molecules is dependent on their position along the filament, suggesting specialized capacities in terms of strain susceptibility and force generation. Three pairs of titin-α and titin-β chains run axially along the filament, intertwining with myosin tails and probably orchestrating the length-dependent activation of the sarcomere. Notably, whereas the three titin-α chains run along the entire length of the thick filament, titin-β chains do not. The structure also demonstrates that MyBP-C bridges thin and thick filaments, with its carboxy-terminal region binding to the myosin tails and directly stabilizing the OFF state of the myosin heads in an unforeseen manner. These results provide a foundation for future research investigating muscle disorders involving sarcomeric components.
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spelling pubmed-106651862023-11-01 Structure of the native myosin filament in the relaxed cardiac sarcomere Tamborrini, Davide Wang, Zhexin Wagner, Thorsten Tacke, Sebastian Stabrin, Markus Grange, Michael Kho, Ay Lin Rees, Martin Bennett, Pauline Gautel, Mathias Raunser, Stefan Nature Article The thick filament is a key component of sarcomeres, the basic units of striated muscle(1). Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases(2). Despite the central importance of the thick filament, its molecular organization remains unclear. Here we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by cryo-electron tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin, titin and myosin-binding protein C (MyBP-C). The arrangement of myosin molecules is dependent on their position along the filament, suggesting specialized capacities in terms of strain susceptibility and force generation. Three pairs of titin-α and titin-β chains run axially along the filament, intertwining with myosin tails and probably orchestrating the length-dependent activation of the sarcomere. Notably, whereas the three titin-α chains run along the entire length of the thick filament, titin-β chains do not. The structure also demonstrates that MyBP-C bridges thin and thick filaments, with its carboxy-terminal region binding to the myosin tails and directly stabilizing the OFF state of the myosin heads in an unforeseen manner. These results provide a foundation for future research investigating muscle disorders involving sarcomeric components. Nature Publishing Group UK 2023-11-01 2023 /pmc/articles/PMC10665186/ /pubmed/37914933 http://dx.doi.org/10.1038/s41586-023-06690-5 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tamborrini, Davide
Wang, Zhexin
Wagner, Thorsten
Tacke, Sebastian
Stabrin, Markus
Grange, Michael
Kho, Ay Lin
Rees, Martin
Bennett, Pauline
Gautel, Mathias
Raunser, Stefan
Structure of the native myosin filament in the relaxed cardiac sarcomere
title Structure of the native myosin filament in the relaxed cardiac sarcomere
title_full Structure of the native myosin filament in the relaxed cardiac sarcomere
title_fullStr Structure of the native myosin filament in the relaxed cardiac sarcomere
title_full_unstemmed Structure of the native myosin filament in the relaxed cardiac sarcomere
title_short Structure of the native myosin filament in the relaxed cardiac sarcomere
title_sort structure of the native myosin filament in the relaxed cardiac sarcomere
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10665186/
https://www.ncbi.nlm.nih.gov/pubmed/37914933
http://dx.doi.org/10.1038/s41586-023-06690-5
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