Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-CC8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. Thick filament based regulatory mechanisms involve either sequestering myosin head into an inactive ordered off state close to the thick filament backbone or releasing them so that they can interact with actin. Strain in the thick filaments, either from a few active heads or passively generated by stretching titin, is presumed to act as a trigger to release inactive heads. While MyBP-C has been presumed to play a role(s) in thick filament activation, details of these mechanisms have been lacking. Here the authors used combination of mechanics and small-angle X-ray diffraction to study the effects of immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C on sarcomere structure and function in permeabilized skeletal muscle. They showed that after titin cleavage, the thin filaments were shorter, a result consistent with thick-thin filament interconnections that can bear strain. Ca2+ sensitivity is reduced at shorter sarcomere lengths, and cross-bridge kinetics are increased across sarcomere lengths at submaximal activation levels, demonstrating a role in cross-bridge kinetics. X-ray structural signatures of the thick filaments suggest that cleavage also shifts myosin heads towards the ON state that is consistent with increased cross-bridge kinetics at submaximal Ca2+ and/or a change in the force transmission pathway. Taken together, they concluded that the MyBP-CC1C7 domains play an important role in contractile performance.
See: Anthony L Hessel, Nichlas M Engels, Michel N Kuehn, Devin Nissen, Rachel L Sadler, Weikang Ma, Thomas C Irving, Wolfgang A Linke, Samantha P Harris. Myosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads. Nat Commun. 2024 Mar 23;15(1):2628. doi: 10.1038/s41467-024-46957-7. PMCID: PMC10960836