Journal Article

Structure of the native myosin filament in the relaxed cardiac sarcomere

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

2023

Overview

The thick filament is a key component of sarcomeres, the basic units of striated muscle 1 . Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases 2 . 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. A cryo-electron tomography study reports the structure of thick myosin filaments of mouse cardiac muscle in the relaxed state in situ and the MyBP-C links that connect them with the surrounding thin actin filaments.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 14 / 14/19 / 631/443/592/75/74/1540 / 631/45/612/1227 / 631/535/1258/1260 / Binding sites / Cardiac muscle / Cardiac Myosins - chemistry / Cardiac Myosins - metabolism / Cardiac Myosins - ultrastructure / Cardiomyopathy / Connectin / Connectin - chemistry / Connectin - metabolism / Connectin - ultrastructure / Cryoelectron Microscopy / Electron Microscope Tomography / Familial hypertrophic cardiomyopathy / Filaments / Heart diseases / Humanities and Social Sciences / Immunoglobulins / Molecular structure / multidisciplinary / Muscle contraction / Muscles / Myocardium - chemistry / Myocardium - cytology / Myocardium - ultrastructure / Myosin / Myosin-binding protein C / Protein C / Proteins / Sarcomeres / Sarcomeres - chemistry / Sarcomeres - metabolism / Sarcomeres - ultrastructure / Science / Science (multidisciplinary) / Tomography