GPCR anterograde trafficking

GPCR 顺行贩运

• 批准号: 10592294
• 负责人: GUANGYU WU
• 金额: $ 35.42万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592294
• 关键词: Address; Adrenergic Receptor; Area; Binding Proteins; Biochemical; Cell membrane; Cell physiology; Cell surface; Destinations; Disease; Drug Design; Drug Targeting; Ear; Endoplasmic Reticulum; G-Protein-Coupled Receptors; Goals; Golgi Apparatus; Hormones; Imaging Techniques; Membrane Proteins; Modeling; Molecular; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Post-Translational Protein Processing; Proteins; Regulation; Research; Rod; Role; Route; Sorting; Ubiquitination; alpha helix; genetic regulatory protein; insight; live cell imaging; novel; programs; protein function; prototype; receptor; response; structural determinants; targeted treatment; trafficking

Summary G protein-coupled receptors (GOCRs) regulate a variety of cell functions and are important targets of therapeutics. A fundamental but poorly understood question in studying GPCRs is how targeted GPCR trafficking is achieved. The overall goal of our research program is to elucidate the molecular mechanisms of nascent GPCR targeting to their functional destinations and to understand the role of targeting in modulating cellular responses to hormones and drugs. Under this broad objective, this proposal will use α2- adrenergic receptors (α2-ARs) as models to address the following two questions which are central to understanding GPCR anterograde trafficking: 1) how newly synthesized GPCRs export from the endoplasmic reticulum (ER) and then transport en route from the ER through the Golgi to the cell surface; and 2) how GPCRs are sorted from one another and from non-GPCR plasma membrane proteins during their traffic along the biosynthetic pathway. The premise of this project is our recent findings that the ER- Golgi-cell surface transport and sorting of α2A-AR and α2B-AR, two closely related, prototypic GPCRs, are coordinated by ufmylation, an ubiquitination-like post-translational modification, and three interacting proteins, C1orf27 (an ER membrane protein), coiled-coil α-helical rod protein 1 (HCR1) and Golgi-localized γ ear-containing ARF-binding protein 3 (GGA3). We will define the novel functions of protein ufmylation and C1orf27 in the ER-Golgi transport and sorting, as well as HCR1 and GGA3 in the post-Golgi traffic and sorting of α2A-AR and α2B-AR, and elucidate the underlying mechanisms. The proposed research is a continuation of our long-standing efforts to study the anterograde trafficking of GPCRs, which have led to the discovery of a number of structural determinants and regulatory proteins essential for GPCR export and sorting. As in the past, we will employ state-of-the-art biochemical, immunochemical and live cell imaging techniques to dissect the mechanistic aspects of GPCR trafficking along the biosynthetic pathway, including maturation, sorting and targeting. These studies will provide important insights into regulation of GPCR export trafficking which is a poorly explored area in the study of the GPCR superfamily.

概括 G蛋白偶联受体（GOCR）调节多种细胞功能，是 治疗。在研究GPCR中的基本但不理解的问题是目标GPCR如何 实现了贩运。我们研究计划的总体目标是阐明分子机制 新生的GPCR靶向其功能目的地，并了解靶向的作用 调节对激素和药物的细胞反应。在这个广泛的目标下，该建议将使用α2- 肾上腺素受体（α2-ar）作为模型，以解决以下两个问题，这些问题是 了解GPCR顺行贩运：1）新合成GPCR的出口如何 内质网（ER），然后从ER穿过高尔基体到细胞表面运输； 2）如何将GPCR彼此分类，并在非GPCR质膜蛋白中分类 它们沿着生物合成途径的交通。该项目的前提是我们最近的发现， α2A-AR和α2B-AR的Golgi细胞表面转运和两个密切相关的原型GPCR是 由ufmylation协调​​，泛素化后翻译后修饰和三个相互作用 蛋白质，C1ORF27（ER膜蛋白），盘绕螺旋α-螺旋杆蛋白1（HCR1）和高尔基体钙化γ 含耳朵的ARF结合蛋白3（GGA3）。我们将定义蛋白质ufmylation的新功能和 er-golgi运输和分类中的C1orf27，以及后高尔基人的HCR1和GGA3， α2A-AR和α2B-AR的排序，并阐明了基本机制。拟议的研究是 继续我们长期以研究GPCR的顺行贩运的努力，这导致了GPCR 发现许多对于GPCR出口所必需的结构决定者和调节蛋白的发现 排序。与过去一样，我们将采用最先进的生化，免疫化学和活细胞成像 剖析沿生物合成途径的GPCR贩运机械方面的技术，包括 成熟，分类和定位。这些研究将为调节GPCR提供重要的见解 出口贩运是在GPCR超家族研究中探索的一个探索区域。