Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments

Significance Cardiac myosin binding protein C (cMyBP-C) is an important regulator of myocardial contraction, but its mechanism of action is unclear. In this study, we examined the structure of thick filaments from the hearts of mice in which the three serine residues that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid to mimic either the nonphosphorylated or phosphorylated state of cMyBP-C. In contrast to earlier work on rat cardiac filaments, the results support a model in which nonphosphorylated cMyBP-C stabilizes the relaxed/superrelaxed ordered “off-state” conformation of the heads while phosphorylation weakens the binding of the heads to the thick filament surface, increasing the probability of interaction with actin.