Structure of the native myosin filament in the relaxed cardiac sarcomere

Davide Tamborrini; Zhexin Wang; Thorsten Wagner; Sebastian Tacke; Markus Stabrin; Michael Grange; Ay Lin Kho; Martin Rees; Pauline Bennett; Mathias Gautel; Stefan Raunser

doi:10.1038/s41586-023-06690-5

Structure of the native myosin filament in the relaxed cardiac sarcomere

Davide Tamborrini, Zhexin Wang, Thorsten Wagner, Sebastian Tacke, Markus Stabrin, Michael Grange, Ay Lin Kho, Martin Rees, Pauline Bennett, Mathias Gautel, Stefan Raunser^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

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.

Original language	English
Pages (from-to)	863-871
Number of pages	9
Journal	Nature
Volume	623
Issue number	7988
DOIs	https://doi.org/10.1038/s41586-023-06690-5
Publication status	Published - 23 Nov 2023

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title = "Structure of the native myosin filament in the relaxed cardiac sarcomere",

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.",

author = "Davide Tamborrini and Zhexin Wang and Thorsten Wagner and Sebastian Tacke and Markus Stabrin and Michael Grange and Kho, {Ay Lin} and Martin Rees and Pauline Bennett and Mathias Gautel and Stefan Raunser",

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AU - Tamborrini, Davide

AU - Wang, Zhexin

AU - Wagner, Thorsten

AU - Tacke, Sebastian

AU - Stabrin, Markus

AU - Grange, Michael

AU - Kho, Ay Lin

AU - Rees, Martin

AU - Bennett, Pauline

AU - Gautel, Mathias

AU - Raunser, Stefan

PY - 2023/11/23

Y1 - 2023/11/23

N2 - 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.

AB - 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.

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Structure of the native myosin filament in the relaxed cardiac sarcomere

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