期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：52
页码：18763-18768
DOI：10.1073/pnas.1413922112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMyosin binding protein-C (MyBP-C) is a regulatory protein of heart muscle. Mutations in MyBP-C are frequently associated with heart disease, but the mechanism of action of MyBP-C is poorly understood. By characterizing the effects of its N-terminal domains on the structures of the thin and thick filaments in contracting heart muscle cells, we showed that MyBP-C stabilizes the ON state of thin filaments and the OFF state of thick filaments. The results lead to a model for the control of heart muscle contraction in which the regulatory functions of the thin and thick filaments are coordinated by MyBP-C, providing an integrated framework for the design and development of therapeutic interventions in heart disease. Myosin binding protein-C (MyBP-C) is a key regulatory protein in heart muscle, and mutations in the MYBPC3 gene are frequently associated with cardiomyopathy. However, the mechanism of action of MyBP-C remains poorly understood, and both activating and inhibitory effects of MyBP-C on contractility have been reported. To clarify the function of the regulatory N-terminal domains of MyBP-C, we determined their effects on the structure of thick (myosin-containing) and thin (actin-containing) filaments in intact sarcomeres of heart muscle. We used fluorescent probes on troponin C in the thin filaments and on myosin regulatory light chain in the thick filaments to monitor structural changes associated with activation of demembranated trabeculae from rat ventricle by the C1mC2 region of rat MyBP-C. C1mC2 induced larger structural changes in thin filaments than calcium activation, and these were still present when active force was blocked with blebbistatin, showing that C1mC2 directly activates the thin filaments. In contrast, structural changes in thick filaments induced by C1mC2 were smaller than those associated with calcium activation and were abolished or reversed by blebbistatin. Low concentrations of C1mC2 did not affect resting force but increased calcium sensitivity and reduced cooperativity of force and structural changes in both thin and thick filaments. These results show that the N-terminal region of MyBP-C stabilizes the ON state of thin filaments and the OFF state of thick filaments and lead to a novel hypothesis for the physiological role of MyBP-C in the regulation of cardiac contractility.
