AGS1 and signal processing by G-proteins

AGS1 和 G 蛋白的信号处理

• 批准号: 7029784
• 负责人: Stephen M. Lanier
• 金额: $ 31.92万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029784
• 关键词: G protein; Saccharomyces cerevisiae; adipose tissue; binding proteins; binding sites; bioenergetics; cell surface receptors; genetic library; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; laboratory rat; mutant; posttranslational modifications; protein isoforms; protein localization; protein protein interaction; receptor coupling; receptor expression; transfection /expression vector

DESCRIPTION (provided by applicant): OVERALL HYPOTHESIS: Signaling efficiency/specificity for heterotrimeric G-protein systems is determined in part by accessory proteins which regulate the efficiency and/or specificity of signal transfer from G-protein coupled receptors (GPCRs) to G-proteins, segregate a signaling complex to microdomains of the cell, regulate the basal activity of the system and/or provide alternative modes of signal input to G-protein signaling systems that operate independent of a typical GPCR. Our objectives are to define such accessory proteins, their mechanism of regulation, their dysfunction in various diseases and their potential as therapeutic targets. We recently identified a group of proteins (Activators of G-protein signaling (AGS) 1-8 that directly influence the activation state of G-proteins independent of a GPCR. AGS proteins interact with different subunits and/or conformations of heterotrimeric G-proteins and selectively regulate different types of G-proteins. This proposal focuses on AGS1, which is unique among the AGS family members. AGS1 is a Ras related protein that regulates heterotrimeric G- protein signaling providing a surprising mechanism for cross talk between small and large (heterotrimeric) G- protein families. A major goal of this application is to understand how AGS1 integrates into cell and organ function. SPECIFIC AIM #1 Define the subcellular location of AGS 1 and the influence of receptor and signal pathway activation on its subcellular location and nucleotide binding state. SPECIFIC AIM #2 Define the domains of AGS 1 required for interaction with and regulation of heterotrimeric G-proteins. SPECIFIC AIM #3 Define the mechanism by which AGS1 regulates signal processing by GPCRs. SPECIFIC AIM #4 Identify and characterize AGS 1 regulators and additional AGS 1 effectors. AGS1 and related accessory proteins provide unexpected mechanisms for regulation of the G-protein activation cycle and have opened up a new area of research related to the cellular role of G-proteins as signal transducers and the cellular functions they regulate. As such, these proteins and the concepts advanced with their discovery provide unexpected avenues for therapeutic development and increased understanding of disease mechanisms.

描述（由申请人提供）：总体假设：异源三聚体 G 蛋白系统的信号传导效率/特异性部分由辅助蛋白决定，辅助蛋白调节从 G 蛋白偶联受体 (GPCR) 到 G 蛋白的信号转移的效率和/或特异性，将信号传导复合物分离到细胞的微结构域，调节系统的基础活性和/或提供信号输入的替代模式 G 蛋白信号系统独立于典型的 GPCR 运行。我们的目标是定义此类辅助蛋白、其调节机制、其在各种疾病中的功能障碍及其作为治疗靶点的潜力。我们最近鉴定了一组蛋白质（G 蛋白信号传导激活剂 (AGS) 1-8，它们独立于 GPCR 直接影响 G 蛋白的激活状态。AGS 蛋白与异源三聚体 G 蛋白的不同亚基和/或构象相互作用，并选择性地调节不同类型的 G 蛋白。本提案重点关注 AGS1，它在 AGS 家族成员中是独一无二的。AGS1 是 Ras 相关蛋白， 调节异三聚体 G 蛋白信号传导，为小和大（异三聚体）G 蛋白家族之间的串扰提供令人惊讶的机制。该应用的一个主要目标是了解 AGS1 如何整合到细胞和器官功能中。具体目标 #1 定义 AGS 1 的亚细胞位置以及受体和信号通路激活对其亚细胞位置和核苷酸结合状态的影响。具体目标#2 定义领域 AGS 1 是与异源三聚体 G 蛋白相互作用并对其进行调节所必需的。具体目标 #3 定义 AGS1 调节 GPCR 信号处理的机制。具体目标#4 识别并表征 AGS 1 调节器和其他 AGS 1 效应器。 AGS1 和相关辅助蛋白为 G 蛋白激活周期的调节提供了意想不到的机制，并开辟了与 G 蛋白的细胞作用相关的新研究领域。 G 蛋白作为信号转导器及其调节的细胞功能。因此，这些蛋白质及其发现所提出的概念为治疗开发和增进对疾病机制的理解提供了意想不到的途径。