Cryo-electron tomography revealed the 3D organization of myosin, titin, and myosin-binding protein C in the native cardiac thick filament, demonstrating that MyBP-C bridges thin and thick filaments.
. 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.
Tamborrini et al. (2023) studied Cardiac sarcomere structure. Cryo-electron tomography was evaluated on 3D molecular architecture of the thick filament. Cryo-electron tomography revealed the 3D organization of myosin, titin, and myosin-binding protein C in the native cardiac thick filament, demonstrating that MyBP-C bridges thin and thick filaments.