EFFECTS OF MYOSIN BINDING PROTEIN-C ON CARDIAC MYOFILAMENT LATTICE SPACING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The myofilament lattice of muscle is made up of thick and thin filaments, which slide past each other during the development of muscle force. The C-terminus of myosin binding protein-C (MyBP-C) is known to bind strongly to thick filament proteins (myosin and titin) and thereby is assumed to physically reinforce the thick filament. In this way, force transmission along the thick filament is facilitated by MyBP-C. The structural and functional roles of the N-terminus of MyBP-C and in particular the phosphorylation sites at the N-terminus, however, are not clear. We propose to use small angle X-ray diffraction to determine the structural effects of the phosphorylation sites at the N-terminus of MyBP-C on the myofilament lattice spacing. We hypothesize that the phosphorylation sites at the N-terminus of MyBP-C bind to or interact with the thin filament. In this way, MyBP-C provides the normal spacing between the thick and thin filaments and facilitates the regular crystalline structure of the myofilament lattice. Using a genetically engineered mouse missing MyBP-C (Null-model), we have previously found that lattice spacing is relatively expanded and in disarray when MyBP-C is missing compared to that when MyBP-C is present (Control-model). These data imply that the N-terminus of the MyBP-C is required to stabilize the myofilament lattice. We now have a new mouse model possessing mutant MyBP-C void of the phosphorylation sites at the N-terminus (AllPminus-model). The planned x-ray experiments will show whether or not phosphorylation sites are important in stabilizing the thick filament.