Collaboarative Research: Protein arginine methylation

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The addition of one or more specific markers to proteins by enzymes known as protein arginine methyltransferases (PRMTs) allows cells to adapt to their ever-changing environments. Biological pathways responsible for development, the response to hormones and viruses, cancer and cardiovascular disease are all impacted by exactly how PRMTs carry out their additions to protein targets. The studies will characterize how the individual members of the PRMT family dictate very specific product formation, for example, one versus two additions, in order to direct the result that is required in the cell. The proposed strategy will integrate both computational modeling and "at-the-bench" biochemical experiments to reveal just how product formation takes place for two members of the PRMT family. The results of these studies will provide foundational information that is required for novel inhibitor development, as well as allow for an understanding of the sophisticated role PRMTs play in cellular signaling. The studies will provide cross training for students in both computational and wet biochemistry experimental strategies, as well as provide the opportunity for undergraduates to receive on-the-job training in the lab, preparing them for the STEM workforce. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Joan Hevel and Dr. Orlando Acevedo to characterize the mechanism of protein arginine monomethylation versus dimethylation using advanced computational and biophysical techniques. The role of sterics, dynamics, and mode of substrate binding in determining which of two different methylation products the protein arginine methyltransferases form will be determined. Information from this study will provide new insight into the sophisticated control of product formation that is required to maintain appropriate patterns of signaling in cells.