Friday, May 27, 2022
5/27/2022
PROJECT SUMMARY The goal of this supplement is to support diversity in NIH missions through training and mentoring a graduate student with a disability. Research proposed under this supplement will be an integral part of the parent m-PI R01 (HL140925) and will be performed in the laboratory of Dr. Samantha Harris, one of the m-PIs, at the University of Arizona. Briefly, goals of the parent R01 are aimed at determining the structure-function relationships of cardiac myosin binding protein-C (cMyBP-C), an essential regulator of heart function, in its interactions with target proteins on the thin filaments of muscle sarcomeres. Specifically, high resolution cryo-EM reconstructions are created that yield information regarding the precise residues and binding interfaces for each of the N’-terminal subdomains of cMyBP-C with proteins on the thin filament (actin, tropomyosin, and troponin). The functional significance of these interactions is then determined using site directed mutagenesis to disrupt or strengthen these interactions followed by assessment of protein function in biochemical assays and force measurements in permeabilized (“skinned”) cardiac muscle cells. The proposed research will contribute to the aims of the parent award by 1) investigating the functional significance of amino acids in the “R-A-S-K” loop of domain C1 on force because these residues were shown by cryo-EM to activate the thin filament; 2) determining the functional effects of phosphorylation at each of the 3 canonical serines, individually and in aggregate, in the regulatory M-domain of cMyBP-C. These experiments are entirely within the scope of the parent proposal, but were chosen as ideal subprojects for mentoring and training a new graduate student to become proficient in technically challenging measurements of force in detergent- permeabilized muscle cells. Results from this funding will therefore increase inclusion and diversity while advancing the aims of the parent proposal by investigating key regulatory effects of cMyBP-C.
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