CAREER: GTPase Switches: Biological Function and Chemical Mechanism

9983736LiGTPases是通过结合和水解GTP调控多种细胞功能的分子开关。然而，在许多情况下，GTPase周期与生物功能耦合的机制尚不清楚。该项目的长期目标是采用多学科的方法来全面了解GTPases的化学原理和生物学功能。这一目标将通过一系列研究和教育举措来实现。本课题主要研究Rab5 GTPase。Rab家族的GTPases调节特定的细胞内运输事件。特别是Rab5定位于早期核内体的细胞质侧，对早期核内体融合很重要，这是内吞作用的必要步骤。本项目将运用细胞生物学、分子生物学、生物化学和生物物理学等实验技术，对Rab5 GTPase活性的机制、新发现的GTPase激活蛋白（GAP）对其的调控及其在核内体融合中的具体功能进行研究。Rab5的结构决定因素对与GAP的特异性相互作用很重要，以及Rab5的结构决定因素对其独特的内在GTPase活性很重要。大量的Rab GTPase不仅具有共同的性质，而且存在个体差异，包括GTPase活性的定量差异和功能特异性的定性差异。这些差异的分子基础尚不清楚。该项目将有助于澄清这些问题，并将对GTPase活性的基本机制以及Rab5在调节核内体融合中的具体功能产生重大影响。在这个职业奖中，目前关于gtpase和gtpase介导的生物学功能的知识和前沿研究将被整合到一个教育计划中，该计划侧重于开发一门名为“多学科方法解决生物学问题”的研究生课程，以探索新的教学方式。本课程将鼓励学生不仅从生物学的角度，而且从化学、物理和数学的角度思考和解决生物学问题。教这门课的有效方法是用具体的例子。在这方面，GTPase蛋白超家族为理解其物理结构、化学动力学和生物学功能原理提供了丰富的资源。本课程将有助于克服障碍，培养跨学科的合作精神，为生物学学生在学术界和工业界的职业生涯做好更好的准备。

9983736LiGTPases are molecular switches that regulate diverse cellular functions via binding and hydrolyzing GTP. In many cases, however, the mechanism by which the GTPase cycle is coupled to biological function is unknown. The long-term goal of this project is to employ a multidisciplinary approach to obtain a thorough understanding of the chemical principle and the biological function of GTPases. This goal will be accomplished through a series of research and education initiatives. The research project focuses on the Rab5 GTPase. The Rab family of GTPases regulates specific intracellular trafficking events. Rab5 in particular is localized to the cytoplasmic side of early endosomes and is important for early endosome fusion, an essential step of endocytosis. In this project, the mechanism of Rab5 GTPase activity, its regulation by a newly identified GTPase-activating protein (GAP), and its specific function in endosome fusion will be investigated by using experimental techniques of cell biology, molecular biology, biochemistry, and biophysics. The structural determinants of Rab5 that are important for the specific interaction with the GAP will be determined, as well as the structural determinants of Rab5 that are important for its unique intrinsic GTPase activity. The large number of Rab GTPases not only share common properties but also show individual differences, including the quantitative difference in GTPase activity and the qualitative difference in functional specificity. The molecular basis of these differences is unclear. This project should help clarify these issues and will have a significant impact on the fundamental mechanism of GTPase activity as well as the specific Rab5 function in regulating endosome fusion. In this Career award, the current knowledge and cutting-edge research on GTPases and GTPase-mediated biological functions will be integrated into an education initiative, which focuses on the development of a graduate course entitled "multidisciplinary approach to biological problems" to explore new ways of teaching. This course will encourage students to think and solve biological problems from the perspectives of not only biology but also chemistry, physics, and mathematics. An effective way to teach this course is to use specific examples. In this regard, the GTPase superfamily of proteins provides a rich resource for understanding the principles of physical structure, chemical kinetics, and biological function. This course will help overcome the barrier and cultivate a collaborative spirit across disciplines and better prepare biology students for careers in academia and industry.