title: Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells.
abstract: 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.
authors.affiliation: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampourakis
authors.affiliation: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Ziqian
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.affiliation: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Yin-Biao
authors.initials: YB
authors.lastname: Sun
authors.affiliation: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom malcolm.irving@kcl.ac.uk.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Irving
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: MYBPC3; cardiac muscle regulation; myosin-binding protein-C