Structural basis for Rab GTPase regulated membrane trafficking

Rab GTPase 调节膜运输的结构基础

• 批准号: 7426873
• 负责人: David G Lambright
• 金额: $ 32.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426873
• 关键词: Base Sequence; Binding; Biogenesis; Biophysics; Cell physiology; Classification; Complex; Crystallization; Cytokinesis; Data; Development; Disease; Elements; Exhibits; Family; Foundations; Funding; GTP Binding; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Human Genome; Hydrolysis; Individual; Link; Lipids; Malignant Neoplasms; Maps; Measurement; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Metabolism; Methodology; Molecular Biology; Molecular Conformation; Motor; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Organelles; Organism; Phosphotransferases; Phylogenetic Pattern; Proteins; Public Health; Publishing; Rate; Recycling; Regulation; Research Personnel; Sequence Alignment; Sequence Homology; Signal Transduction; Sorting - Cell Movement; Source; Specificity; Structure; System; Systems Biology; Testing; Therapeutic; Tubular formation; Virulence Factors; base; cancer type; cell growth; design; high throughput screening; insight; member; membrane biogenesis; multidisciplinary; novel; programs; rab GTP-Binding Proteins; spatiotemporal; structural biology

DESCRIPTION (provided by applicant): Rab GTPases are essential regulators of diverse cellular processes including membrane trafficking, cell growth, organelle biogenesis, membrane remodeling, signaling transduction, and development. Rab GTPases as well as their regulatory factors and effectors have been implicated in genetically linked disorders, complex disease states such as type II diabetes and cancer, and are targets of virulence factors from pathogenic organisms. Many Rab GTPase have spatially and temporally overlapping distributions within the dynamic and highly interconnected network of tubular-vesicular organelles that comprise the biosynthetic, endocytic, and recycling systems. The functions of Rab GTPases are further coordinated through multivalent proteins and complexes with two or more distinct Rab GTPase binding domains, each of which has a unique specificity profile for subsets of Rab GTPases. With 60 distinct proteins encoded in the human genome, Rab GTPases represent the largest and most complex branch of the Ras superfamily. Characterizing interactions with structurally diverse effectors and regulatory factors, determining specificities, and deciphering the elaborate encoding of recognition determinants represent a critically important challenge. During the previous funding period, we developed, optimized, and successfully tested a multidisciplinary strategy for solving the recognition problem at the level of the Rab GTPase family. The long term objectives of this renewal application are to: i) generalize this approach to as many effectors, regulatory factors, and accessory proteins as possible; and ii) extend the methodology to incorporate identification of interaction partners for candidate Rab interacting proteins. To achieve these objectives, we will: (Aim 1) quantitatively profile the specificity of effectors and regulatory factors for the Rab GTPase family; (Aim 2) investigate the underlying structural bases; (Aim 3) identify the major determinants of the observed specificity. This combination of experimental strategies will provide critical information on the specificity profiles, structural bases, and sequence determinants underlying the interaction of Rab GTPases with effectors, regulatory factors, and accessory proteins. Relevance to Public Health: These studies will reveal novel insights into the mechanisms for regulation of membrane trafficking, cell growth, and metabolism. The resulting information may prove useful in the design of mechanism based therapeutics for treatment of cancer and type II diabetes.

描述（由申请人提供）：Rab GTP 酶是多种细胞过程的重要调节剂，包括膜运输、细胞生长、细胞器生物发生、膜重塑、信号转导和发育。 Rab GTP 酶及其调节因子和效应子与遗传相关疾病、II 型糖尿病和癌症等复杂疾病状态有关，并且是病原生物毒力因子的目标。许多 Rab GTP 酶在包含生物合成、内吞和再循环系统的管状囊泡细胞器的动态且高度互连的网络中具有空间和时间重叠的分布。 Rab GTPases 的功能通过多价蛋白和复合物与两个或多个不同的 Rab GTPase 结合域进一步协调，每个结合域对 Rab GTPases 子集都有独特的特异性。 Rab GTP 酶在人类基因组中编码了 60 种不同的蛋白质，代表了 Ras 超家族中最大、最复杂的分支。表征与结构多样的效应器和调节因子的相互作用、确定特异性以及破译识别决定因素的复杂编码是一项极其重要的挑战。在上一个资助期间，我们开发、优化并成功测试了一种多学科策略，用于解决 Rab GTPase 家族水平的识别问题。该更新应用的长期目标是： i) 将这种方法推广到尽可能多的效应子、调节因子和辅助蛋白； ii) 扩展该方法以纳入候选 Rab 相互作用蛋白的相互作用伙伴的鉴定。为了实现这些目标，我们将：（目标 1）定量分析 Rab GTPase 家族效应子和调控因子的特异性； （目标 2）调查潜在的结构基础； （目标 3）确定观察到的特异性的主要决定因素。这种实验策略的组合将提供有关 Rab GTPases 与效应子、调节因子和辅助蛋白相互作用的特异性概况、结构基础和序列决定因素的关键信息。与公共卫生的相关性：这些研究将揭示膜运输、细胞生长和代谢调节机制的新见解。由此产生的信息可能有助于设计基于机制的治疗癌症和 II 型糖尿病的疗法。