title: Structure and interactions of myosin-binding protein C domain C0: cardiac-specific regulation of myosin at its neck?
abstract: Myosin-binding protein C (MyBP-C) is a multidomain protein present in the thick filaments of striated muscles and is involved in both sarcomere formation and contraction regulation. The latter function is believed to be located at the N terminus, which is close to the motor domain of myosin. The cardiac isoform of MyBP-C is linked to hypertrophic cardiomyopathy. Here, we use NMR spectroscopy and biophysical and biochemical assays to study the three-dimensional structure and interactions of the cardiac-specific Ig-like domain C0, a part of cardiac MyBP-C of which little is known. The structure confirmed that C0 is a member of the IgI class of proteins, showing many of the characteristic features of this fold. Moreover, we identify a novel interaction between C0 and the regulatory light chain of myosin, thus placing the N terminus of the protein in proximity to the motor domain of myosin. This novel interaction is disrupted by several cardiomyopathy-linked mutations in the MYBPC3 gene. These results provide new insights into how cardiac MyBP-C incorporates in the sarcomere and how it can contribute to the regulation of muscle contraction.
authors.affiliation: Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Joyce
authors.initials: J
authors.lastname: Ratti
authors.forename: Elena
authors.initials: E
authors.lastname: Rostkova
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.forename: Mark
authors.initials: M
authors.lastname: Pfuhl
mesh_terms: D002152:Calorimetry, Differential Scanning; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D018994:Myosin Light Chains / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D018994:Myosin Light Chains; D009218:Myosins; D000099163:Myosin Binding Protein C