biostudies-literatureHessel ALNHLBI NIH HHSNIGMS NIH HHS2628https://www.ebi.ac.uk/biostudies/studies/S-EPMC10960836biostudies-literatureUnknown15(1)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-C^C8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-C^C1C7) 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. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-C^C1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-C^C1C7 to myofilament force production and regulation.Nature communicationsMyosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.PMC10960836P30 GM138395T32 HL007249P41 GM103622Linke WANissen DEngels NMKuehn MNHarris SPHessel ALSadler RLIrving TCMa WfalseMyosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads.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-C^C8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-C^C1C7) 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. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-C^C1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-C^C1C7 to myofilament force production and regulation.2024-01-01T00:00:00Z2024 Mar2025-04-26T12:02:50.515Z2025-04-06T13:55:16.624ZS-EPMC109608363852179410.1038/s41467-024-46957-7