Beyond the N-terminus: Emerging regulatory roles of the middle and C-terminal domains of cardiac myosin binding protein-C

Cardiac myosin binding protein-C (cMyBP-C) is a key regulator of sarcomere structure and contractile function that modulates actomyosin interactions to control the speed and strength of cardiac muscle contraction and relaxation. As an integral part of the sarcomeric machinery, this modular protein has been extensively studied; however, the regulatory contributions of its middle and C-terminal regions remain incompletely understood. This review highlights the structural organization and emerging roles of key cMyBP-C domains, including multiple phosphorylation sites in the N-terminal M-domain, the flexible C4-C5 linker, the cardiac-specific C5 loop, and the extended linker between domains C9 and C10. We discuss how N-terminal domains interact with actin and myosin subfragments (S1/S2) to influence contractile dynamics, particularly through phosphorylation-dependent modulation of actomyosin interactions. We further examine the middle domains (C4-C6), which contain the C4-C5 linker and the C5 loop, originally proposed to function primarily as structural spacers but are now increasingly implicated in regulating cMyBP-C function. The C-terminal domains, particularly C7-C10, are essential for anchoring cMyBP-C to the thick filament's C-zone, though additional functional roles remain to be uncovered. Post-translational modifications, including phosphorylation, S-glutathionylation, nitrosylation, and acetylation, are discussed in the context of cardiac stress and disease, while recognizing that their physiological significance and potential interplay remain incompletely understood. Finally, we highlight the current limitations in visualizing dynamic cMyBP-C interactions and emphasize the need for integrative structural, biochemical, and in vivo studies to fully elucidate the regulatory network orchestrated by this multi-domain sarcomeric regulator. Improved mechanistic understanding may ultimately reveal therapeutic opportunities for cardiomyopathies associated with mutations in MYBPC3 and dysregulated cMyBP-C signaling.