Collaborative Research: Protein Arginine Methylation

被称为蛋白质精氨酸甲基转移酶(PRMTs)的酶将一个或多个特定的标记物添加到蛋白质上，使细胞能够适应不断变化的环境。负责发育、对激素和病毒的反应、癌症和心血管疾病的生物途径都受到PRMT如何将其添加到蛋白质靶点的确切方式的影响。这些研究将描述PRMT家族的各个成员如何决定非常特定的产物形成，例如，一次加成与两次相加，以指导细胞所需的结果。建议的策略将整合计算建模和现场测试。生物化学实验，揭示PRMT家族中两个成员的产品形成过程。这些研究的结果将提供开发新型抑制剂所需的基础信息，并允许理解PRMT在细胞信号转导中所起的复杂作用。这些研究将为学生提供计算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，为他们进入STEM劳动力做好准备。通过这一奖项，化学部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研究蛋白质精氨酸单甲基化与双甲基化的机制。在决定蛋白质精氨酸甲基转移酶形成两种不同甲基化产物中的哪一种时，空间构型、动力学和底物结合方式的作用将被确定。这项研究的信息将为复杂的产物形成控制提供新的见解，这是在细胞中维持适当的信号模式所必需的。

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.