Structure of the native myosin filament in the relaxed cardiac sarcomere

Tamborrini, Davide and Wang, Zhexin and Wagner, Thorsten and Tacke, Sebastian and Stabrin, Markus and Grange, Michael and Kho, Ay Lin and Rees, Martin and Bennett, Pauline and Gautel, Mathias and Raunser, Stefan (2023) Structure of the native myosin filament in the relaxed cardiac sarcomere. Nature. ISSN 0028-0836

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Abstract

The thick filament is a key component of sarcomeres, the basic units of striated muscle1. Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases2. 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.

Item Type: Article
Subjects: Impact Archive > Multidisciplinary
Depositing User: Managing Editor
Date Deposited: 10 Nov 2023 05:02
Last Modified: 10 Nov 2023 05:02
URI: http://research.sdpublishers.net/id/eprint/3473

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