Dissecting the N-terminal myosin binding site of human cardiac myosin-binding protein C. Structure and myosin binding of domain C2

摘要: Abstract Myosin-binding protein C (MyBP-C) binds to myosin with two binding sites, one close the N terminus and other at terminus. Here we present solution structure of part N-terminal site, third immunoglobulin domain cardiac isoform human MyBP-C (cC2) together a model its interaction myosin. Domain cC2 has β-sandwich expected from member fold. The C-terminal is very closely related telokin, fragment light chain kinase. also contains cysteines on neighboring strands F G, which would be able form disulfide bridge in similar position as telokin. Using NMR spectroscopy isothermal titration calorimetry demonstrate that alone myosin, S2Δ, low affinity (kD = 1.1 mm) but exhibits highly specific site. This consists surface C′CFGA′ β-sheet, includes Glu301, residue mutated Gln disease familial hypertrophic cardiomyopathy. site S2 was identified by combination experiments S2Δ containing cardiomyopathy-linked mutation R870H molecular modeling. lowers changes arrangement side chains interface. Our cC2-S2Δ complex gives first glimpse details MyBP-C-myosin interaction. this suggest most key interactions are between polar amino acids, explaining why mutations E301Q could involved We expect will stimulate future research further refine their importance for