Collaborative Research: Protein Arginine Methylation

通过蛋白质精氨酸甲基转移酶（PRMTs）向蛋白质中添加一种或多种特定标记物，使细胞能够适应不断变化的环境。负责发育的生物途径、对激素和病毒的反应、癌症和心血管疾病都受到prmt如何向蛋白质靶标添加的确切影响。这些研究将描述PRMT家族的个体成员如何决定非常特定的产物形成，例如，一个或两个添加，以指导细胞中所需的结果。所提出的策略将集成计算建模和“在台上”。生化实验揭示了PRMT家族的两个成员是如何形成产品的。这些研究的结果将为开发新的抑制剂提供必要的基础信息，并允许理解PRMTs在细胞信号传导中的复杂作用。这些研究将为学生提供计算生物化学和湿生物化学实验策略的交叉培训，并为本科生提供在实验室接受在职培训的机会，为STEM劳动力做好准备。有了这个奖项，化学部门的生命过程化学项目资助Joan Hevel博士和Orlando Acevedo博士使用先进的计算和生物物理技术来表征蛋白质精氨酸单甲基化与二甲基化的机制。在决定蛋白精氨酸甲基转移酶形成的两种不同甲基化产物中的哪一种时，立体结构、动力学和底物结合模式的作用将被确定。这项研究的信息将为维持细胞中适当的信号传导模式所需的产物形成的复杂控制提供新的见解。

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.