CAREER: GTPase Switches: Biological Function and Chemical Mechanism

职业：GTP 酶开关：生物功能和化学机制

• 批准号: 9983736
• 负责人: Guangpu Li
• 金额: $ 49.95万
• 依托单位: University of Oklahoma Health Sciences Center
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9983736&HistoricalAwards=false
• 关键词: CAREER; GTPase; Switches; Biological; Function

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.

9983736LiGTP 酶是通过结合和水解 GTP 调节多种细胞功能的分子开关。 然而，在许多情况下，GTP 酶循环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方法来全面了解 GTP 酶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。 该研究项目的重点是 Rab5 GTPase。 GTPases 的 Rab 家族调节特定的细胞内运输事件。 Rab5 特别定位于早期内体的细胞质侧，对于早期内体融合（内吞作用的重要步骤）非常重要。 本项目将利用细胞生物学、分子生物学、生物化学和生物物理学等实验技术，研究Ra​​b5 GTPase活性的机制、新发现的GTPase激活蛋白（GAP）对其的调控及其在内体融合中的具体功能。 将确定对于与 GAP 特异性相互作用重要的 Rab5 结构决定因素，以及对于其独特的内在 GTPase 活性重要的 Rab5 结构决定因素。大量的Rab GTPase不仅具有共同的性质，而且表现出个体差异，包括GTPase活性的量的差异和功能特异性的质的差异。 这些差异的分子基础尚不清楚。 该项目应有助于阐明这些问题，并将对GTPase活性的基本机制以及调节内体融合的特定Rab5功能产生重大影响。 在本次职业奖中，当前关于GTP酶和GTP酶介导的生物功能的知识和前沿研究将被整合到一项教育计划中，该计划重点开发题为“生物问题的多学科方法”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思考和解决生物学问题，还从化学、物理和数学的角度思考和解决生物学问题。 教授本课程的一个有效方法是使用具体的例子。 在这方面，GTP酶蛋白超家族为理解物理结构、化学动力学和生物功能的原理提供了丰富的资源。 本课程将有助于克服障碍并培养跨学科的协作精神，并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。