GBeta5/RGS proteins and GPCR signaling

Gbeta5/RGS 蛋白和 GPCR 信号传导

• 批准号: 7904747
• 负责人: JOHN E SONDEK
• 金额: $ 27.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904747
• 关键词: Activities of Daily Living; Binding; Binding Proteins; Biochemical; Boxing; Complement; Complex; Crystallography; Data; Event; Exhibits; Free Will; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP Binding; GTP-Binding Protein Regulators; GTP-Binding Proteins; GTPase-Activating Proteins; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Heterotrimeric G Protein Subunit; Heterotrimeric GTP-Binding Proteins; Length; Lobe; Mediating; Membrane; Molecular Models; N-terminal; Physiological; Protein Subunits; Proteins; RGS Domain; RGS Proteins; RGS9 protein; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Structure; Surface; System; Testing; Treatment Protocols; Work; base; design; dimer; empowered; molecular modeling; novel; programs; protein complex; reconstitution

DESCRIPTION (provided by applicant): The Regulator of G protein Signaling (RGS) proteins originally were identified as GTPase-activating proteins (GAPs) for heterotrimeric G protein ? subunits. However, many RGS proteins possess highly- conserved domains in addition to the signature RGS box, which empower a multifunctional character that underlies poorly understood but physiologically important interactions among components of heterotrimeric G protein signaling cascades as well as with other signaling pathways. The R7 subfamily of RGS proteins possess a distinctive G-?-like (GGL) domain that mediates specific and obligate heterodimer formation with the atypical G protein subunit, G?5, suggesting that these signaling proteins exhibit functions similar to conventional G?? dimers. Our recently refined crystal structure of G?5/RGS9 support this idea and provides a framework for testing hypotheses related to various binding interfaces of this dimer that likely subserve the organization and integration of higher-order, multifunctional G protein/GPCR/RGS complexes. Consequently, we propose to: 1) use crystallography and mutational analyses to define the complete functionality and G? specificity of RGS domains within full-length G??5/R7 dimers; 2) extend our understanding of the functional and structural relationships between G??5/R7 dimers and their anchoring proteins, R9AP and R7BP; and 3) quantify the functional capacities of G??5/R7 dimers to interact with GDP- G? subunits and GPCRs using reconstituted systems of purified components. While it is clear that R7 proteins are required for proper signaling mediated by G protein-coupled receptors under a variety of physiological settings, the roles of these proteins in coordinating these signaling events are relatively poorly understood. The work proposed here is designed to place R7 proteins within a detailed structural and functional context with respect to G protein-coupled receptors and heterotrimeric G proteins. It is anticipated that these studies will then be used to guide treatment regimens in cases where coordinated signaling mediated by R7 proteins has failed.

描述（由申请人提供）：G蛋白信号传导（RGS）蛋白的调节剂最初被鉴定为GTPase激活蛋白（GAPS）的异源三聚体G蛋白？亚基。然而，许多RGS蛋白除了签名RGS框外还具有高度保守的结构域，该框架赋予了多功能特征，该特征是理解较低但生理上重要的相互作用的多功能特征，但在生理上重要的相互作用在异三聚体G蛋白信号级联和其他信号通路之间具有重要的相互作用。 RGS蛋白的R7亚家族具有独特的g - ？ - 喜欢（GGL）结构域，该结构域介导了特定和强制性异二聚体形成与非典型G蛋白亚基G？5，这表明这些信号蛋白表现出与常规G的功能相似的作用？二聚体。我们最近精制的G？5/RGS9的晶体结构支持了这一想法，并为测试与该二聚体的各种结合接口有关的假设提供了一个框架，该假设可能会提供高阶，多功能G蛋白/GPCR/RGS复合物的组织和整合。因此，我们建议：1）使用晶体学和突变分析来定义完整的功能和G？全长G ?? 5/R7二聚体内RGS域的特异性； 2）扩展我们对G ?? 5/R7二聚体之间的功能和结构关系的理解及其锚定蛋白R9AP和R7BP； 3）量化G ?? 5/R7二聚体的功能能力与GDP-G相互作用？使用纯化组件的重构系统的亚基和GPCR。虽然很明显，在各种生理环境下，由G蛋白偶联受体介导的适当信号蛋白需要R7蛋白，但这些蛋白质在协调这些信号事件中的作用相对较少了解。此处提出的工作旨在将R7蛋白放置在G蛋白偶联受体和异三聚体G蛋白方面的详细结构和功能上下文中。可以预计，这些研究将用于指导治疗方案，而在R7蛋白介导的协调信号传导失败的情况下。