Structure of mavacamten- free human cardiac thick filaments within the sarcomere by cryoelectron tomography

• 成果类型: Article
• 署名作者: Chen, Liang; Liu, Jun; Rastegarpouyani, Hosna; Janssen, Paul M. L.; Pinto, Jose R.; Taylor, Kenneth A.
• 署名单位: State University System of Florida; Florida State University; Yale University; Yale University; State University System of Florida; Florida State University; University System of Ohio; Ohio State University; State University System of Florida; Florida State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8656
• DOI: 10.1073/pnas.2311883121
• 发表日期: 2024-02-27
• 关键词: binding-protein-c; light-chain phosphorylation; super-relaxed state; myosin-filaments; muscle myosin; stretch activation; heavy-meromyosin; atomic model; mybp-c; contraction

摘要

Heart muscle has the unique property that it can never rest; all cardiomyocytes contract ducing the required force. Thick filaments contain additional nonmyosin proteins, myosin- binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3- D image reconstruction of frozen- hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429 angstrom repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin- binding protein C. We think that this hierarchy of control explains many of the effects of length- dependent activation as well as stretch activation in cardiac muscle control.