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Science 337 (6099): 1215-1218

Copyright © 2012 by the American Association for the Advancement of Science

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

M. J. Previs,1 S. Beck Previs,1 J. Gulick,2 J. Robbins,2 D. M. Warshaw1,*

Abstract: The heart’s pumping capacity results from highly regulated interactions of actomyosin molecular motors. Mutations in the gene for a potential regulator of these motors, cardiac myosin-binding protein C (cMyBP-C), cause hypertrophic cardiomyopathy. However, cMyBP-C’s ability to modulate cardiac contractility is not well understood. Using single-particle fluorescence imaging techniques, transgenic protein expression, proteomics, and modeling, we found that cMyBP-C slowed actomyosin motion generation in native cardiac thick filaments. This mechanical effect was localized to where cMyBP-C resides within the thick filament (i.e., the C-zones) and was modulated by phosphorylation and site-specific proteolytic degradation. These results provide molecular insight into why cMyBP-C should be considered a member of a tripartite complex with actin and myosin that allows fine tuning of cardiac muscle contraction.

1 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA.
2 Department of Pediatrics and the Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

* To whom correspondence should be addressed. E-mail: david.warshaw{at}uvm.edu

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