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.

SUBMITTER: Tamborrini D 

PROVIDER: S-EPMC10665186 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature