Structure and Function of GDI

GDI的结构和功能

• 批准号: 7677214
• 负责人: William Edward Balch
• 金额: $ 12.19万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677214
• 关键词: Area; Binding; Biochemical; Biological Assay; Biology; Bos taurus; Brain; Cattle; Cell Proliferation; Cells; Cellular biology; Choroideremia; Chromosome Pairing; Complex; Condition; Disease; Endosomes; Eye diseases; Foundations; Funding; Golgi Apparatus; Guanine Nucleotide Dissociation Inhibitors; Hematopoietic; Knowledge; Link; Lipid Bilayers; Lipids; Malignant Neoplasms; Mediating; Membrane; Membrane Protein Traffic; Mental Retardation; Molecular; Molecular Analysis; Molecular Chaperones; Monomeric GTP-Binding Proteins; Pathway interactions; Phosphotransferases; Physiological; Play; Process; Progress Reports; Protein Isoforms; Proteins; Publishing; Rab3a guanine nucleotide dissociation inhibitor; RabGDI; Receptor Signaling; Recycling; Regulation; Reporter; Retrieval; Role; Signal Pathway; Site; Solid; Steroid Receptors; Steroids; Structure; Structure-Activity Relationship; Synapses; System; Transmembrane Transport; Vesicle; base; chaperone machinery; insight; interest; prenyl; rab GTP-Binding Proteins; steroid hormone; steroid hormone receptor; trafficking

DESCRIPTION (provided by applicant): Guanine nucleotide dissociation inhibitor (GDI) plays an essential role in the recycling of Rab proteins, small GTPases that regulate membrane vesicle traffic. We have established that Rab recycling involves a Hsp90-GDI chaperone system. The principle focus of this proposal is to understand the biochemical and molecular basis for the function of the Hsp90 chaperone complex in mediating GDI-Rab protein interaction during Rab recycling.We propose 3 specific aims to provide structural, molecular and biochemical insight into the structure/function relationships between GDI, Rab and their sequential physiological protein interactions with components of the Hsp90 chaperone machinery. We will explore the general hypothesis that transfer of Rab from the lipid bilayer to GDI during recycling involves a Hsp90 chaperone complex in an analogous fashion to the manner in which steroid hormone receptors (SHR) complexes are primed for steroid hormone binding by the Hsp90 chaperone complex. Specific Aim 1 will continue to expand our structural studies to determine the molecular basis of GDI function. These studies will include determining the structure of beta and delta GDI isoforms, determining the structure of the native alpha GDI-Rab3A-GG complex isolated from bovine brain, and determining structure(s) of alpha GDI-Hsp90 chaperone complexes. Specific Aim 2 will apply biochemical approaches to identify and characterize the basis for the interaction of GDI with components of the Hsp90 chaperone complex. These studies will take advantage of the extensive knowledge of the role of the Hsp90 chaperone complexes in regulation of SHR and signaling kinase pathways. Specific Aim 3 will take a molecular approach to identify the basis for protein interactions between GDI, Rab and the Hsp90 chaperone complex. These three aims will contribute significantly to advancing our basic understanding of the general role of GDI and Rab GTPases in membrane transport, an area of high interest to contemporary cell biology. They will provide insight into a broad spectrum of diseases given the role of GDI and Rab in mental retardation, diseases of hematopoietic lineage, eye disease and cell proliferation (cancer) related to changes in Hsp90 regulated signaling pathways.

描述（由申请人提供）：鸟嘌呤核苷酸解离抑制剂（GDI）在RAB蛋白的回收中起着至关重要的作用，该蛋白，调节膜囊泡流量的小GTP酶。我们已经确定RAB回收涉及HSP90-GDI伴侣系统。该建议的主要重点是了解Hsp90伴侣复合物在介导GDI-rab蛋白相互作用中的功能的生化和分子基础。我们提出了3个特定目的，以提供结构，分子和生化洞察力的特定目的GDI，RAB及其顺序生理蛋白与HSP90伴侣机械组件之间的功能关系。我们将探讨一个总体假设，即在回收过程中，Rab从脂质双层转移到GDI涉及HSP90伴侣复合物，以类似的方式与类固醇激素受体（SHR）复合物相似的方式，以通过HSP90伴侣蛋白伴侣结合进行类固醇激素的络合物。 。具体目标1将继续扩展我们的结构研究，以确定GDI功能的分子基础。这些研究将包括确定β和Delta GDI同工型的结构，确定从牛脑分离的天然alpha gdi-rab3a-gg络合物的结构，并确定alpha GDI-HSP90伴侣蛋白复合体的αGDI-HSP90伴侣的结构。具体目标2将采用生化方法来识别和表征GDI与HSP90伴侣复合物的组成部分相互作用的基础。这些研究将利用HSP90伴侣复合物在SHR和信号激酶途径调节中的作用的广泛了解。特定的目标3将采用分子方法来识别GDI，RAB和HSP90伴侣复合物之间蛋白质相互作用的基础。这三个目标将对我们对GDI和RAB GTPases在膜运输中的一般作用的基本理解做出重大贡献，这是当代细胞生物学引起的浓厚兴趣领域。鉴于GDI和RAB在智力低下，造血谱系疾病，眼部疾病和细胞增殖（癌症）与HSP90调控信号通路的变化有关的疾病，他们将提供有关广泛疾病的洞察力。