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. Cardiac myosin binding protein-C (cMyBP-C) phosphorylation changes in heart failure and may be a significant modulator of cardiac function. We have recently shown that both genetic ablation and protein kinase A-mediated (PKA) phosphorylation of cMyBP-C appear to result in radial or azimuthal displacement of myosin cross-bridges, such that cross-bridges are located further from the surface of the thick filament of myosin and closer to the thin filament of actin. Reversible PKA phosphorylation of myofibrillar proteins, such as cMyBP-C, involves the addition of a negatively charged phosphate (PO4) molecule on a serine or threonine residue, which induces a conformational change in the structure of the protein. While we have found PKA phosphorylation of cMyBP-C to modulate the disposition and availability of cross-bridges to actin, it remains unresolved whether or not this mechanism of cMyBP-C function is attributed to the negative charge associated with phosphorylation. To test this, we assessed the intensities of equatorial reflections (I11/I10) using low-angle X-ray diffraction to determine the position of cross-bridges in myocardium from four lines of mutant mice. The mutations include four pertinent states of myofibrillar phosphorylation: non-phosphorylatable cMyBP-C mutant protein, constitutively-phosphorylated cMyBP-C mutant protein, normal cMyBP-C protein, and normal cMyBP-C expressed with non-phosphorylatable cardiac troponin I (cTnI) since cTnI phosphorylation also affects contraction. We hypothesize that the negative charge associated with phosphorylation of PKA sites in cMyBP-C will be sufficient to relieve a physical constraint on cross-bridges, possibly by disrupting cMyBP-C binding to the S2-region of myosin.
| Orgel, Joseph P R O; Sella, Ido; Madhurapantula, Rama S et al. (2017) Molecular and ultrastructural studies of a fibrillar collagen from octocoral (Cnidaria). J Exp Biol 220:3327-3335 |
| Yazdi, Aliakbar Khalili; Vezina, Grant C; Shilton, Brian H (2017) An alternate mode of oligomerization for E. coli SecA. Sci Rep 7:11747 |
| Sullivan, Brendan; Robison, Gregory; Pushkar, Yulia et al. (2017) Copper accumulation in rodent brain astrocytes: A species difference. J Trace Elem Med Biol 39:6-13 |
| Morris, Martha Clare (2016) Nutrition and risk of dementia: overview and methodological issues. Ann N Y Acad Sci 1367:31-7 |
| Robison, Gregory; Sullivan, Brendan; Cannon, Jason R et al. (2015) Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation. Metallomics 7:748-55 |
| Gelfand, Paul; Smith, Randy J; Stavitski, Eli et al. (2015) Characterization of Protein Structural Changes in Living Cells Using Time-Lapsed FTIR Imaging. Anal Chem 87:6025-31 |
| Liang, Wenguang G; Ren, Min; Zhao, Fan et al. (2015) Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme. J Mol Biol 427:1345-1358 |
| Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39 |
| Nobrega, R Paul; Arora, Karunesh; Kathuria, Sagar V et al. (2014) Modulation of frustration in folding by sequence permutation. Proc Natl Acad Sci U S A 111:10562-7 |
| Jiao, Lianying; Ouyang, Songying; Shaw, Neil et al. (2014) Mechanism of the Rpn13-induced activation of Uch37. Protein Cell 5:616-30 |
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