The cardiac myosin binding protein-C–myosin S2 interaction: modulation of cardiac contractility and its role in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder caused primarily by pathogenic variants in sarcomeric genes encoding β-cardiac myosin heavy chain ( MYH7 ) and cardiac myosin binding protein-C ( MYBPC3 ; cMyBP-C). cMyBP-C plays a central role in the modulation of contractility by interacting with the subfragment 2 (S2) region of myosin in a phosphorylation-dependent manner, thereby tuning myosin head availability. The proximal S2 region, enriched in negatively charged residues, facilitates reversible sequestration of myosin heads into the energy-conserving super-relaxed (SRX) state, which is characterized by reduced ATPase activity. Through its phosphorylation-sensitive M-domain, cMyBP-C stabilizes this inhibited state by binding S2 when myosin heads are folded back. In response to physiological stress, phosphorylation of cMyBP-C weakens this interaction, promoting release of myosin heads from the SRX state and enhancing contractility. Pathogenic mutations in MYH7 or MYBPC3 disrupt this modulatory mechanism, shifting the equilibrium toward increased myosin head availability, hypercontractility, and inefficient ATP utilization, all hallmarks of HCM. While conventional therapies do not directly target these molecular defects, recently developed myosin inhibitors such as mavacamten and aficamten demonstrate therapeutic potential by modulating sarcomere function, although their efficacy is limited to specific patient subsets. This review examines the structural and functional dynamics of the cMyBP-C–myosin S2 interaction as a key determinant of cardiac muscle contraction. We highlight roles in SRX stabilization, contractile control, and disease pathogenesis, and discuss emerging strategies, including gene therapy, targeted peptides, and protein replacement, to restore sarcomere function. A detailed molecular understanding of this interaction may inform the development of disease-modifying therapies for HCM.