Molecular Mechanics of Cardiac Myosin-Binding Protein C in Native Thick Filaments

Abstract

Understanding a Broken Heart Cardiac myosin-binding protein C (cMyBP-C) is a thick filament–associated sarcomeric protein that modulates cardiac contractility in a phosphorylation-dependent manner; mutations in the MYBC3 gene are the leading cause of hypertrophic cardiomyopathy. Previs et al. (p. 1215 , published online 23 August; see the Perspective by Burghardt and Ajtai ) have isolated native myosin thick filaments from transgenic mouse hearts, which retained the spatial distribution of cMyBP-C in the thick filament. Imaging of a single actin filament being propelled along the thick filament showed that the N-terminal 29-kD domain of cMyBP-C slows actomyosin motion in parts of the thick filament corresponding to the C-zones in which the thick filaments are cross-bridged. This effect on actomyosin contractility was tuned by graded phosphorylation of four serines adjacent to the 29-kD domain. The findings may explain the appearance of a cMyBP-C fragment in the serum of patients with cardiac ischemia and why cMyBP-C haploinsufficiency associated with cardiomyopathy patients might trigger a hypertrophic response.