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 and Stefan Raunser ()
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Davide Tamborrini: Max Planck Institute of Molecular Physiology
Zhexin Wang: Max Planck Institute of Molecular Physiology
Thorsten Wagner: Max Planck Institute of Molecular Physiology
Sebastian Tacke: Max Planck Institute of Molecular Physiology
Markus Stabrin: Max Planck Institute of Molecular Physiology
Michael Grange: Max Planck Institute of Molecular Physiology
Ay Lin Kho: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Kings College London BHF Centre of Research Excellence
Martin Rees: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Kings College London BHF Centre of Research Excellence
Pauline Bennett: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Kings College London BHF Centre of Research Excellence
Mathias Gautel: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Kings College London BHF Centre of Research Excellence
Stefan Raunser: Max Planck Institute of Molecular Physiology

Nature, 2023, vol. 623, issue 7988, 863-871

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06690-5

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