GPCR anterograde trafficking

GPCR 顺行贩运

• 批准号: 10388443
• 负责人: GUANGYU WU
• 金额: $ 23万
• 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/10388443
• 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 - Cell Movement; Structure; Ubiquitination; genetic regulatory protein; insight; live cell imaging; novel; programs; protein function; receptor; response; 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.

摘要 G蛋白偶联受体(GOCR)调节多种细胞功能，是 治疗学。研究GPCRs的一个基本但鲜为人知的问题是如何针对GPCRs 人口贩运就实现了。我们研究计划的总体目标是阐明分子机制。 将新生的GPCR靶向它们的功能目的地，并理解靶向在 调节细胞对激素和药物的反应。在这一大目标下，该提案将使用α2- 肾上腺素能受体(α2-AR)作为模型来解决以下两个核心问题 了解GPCR顺势贩运：1)新合成的GPCRs如何从 内质网(ER)，然后从内质网通过高尔基体运输到细胞表面； 2)GPCRs是如何相互分离的，以及如何从非GPCR质膜蛋白中分离出来的 它们在生物合成途径上的交通。这个项目的前提是我们最近的发现，ER- α2A-AR和α2B-AR是两个密切相关的原型GPCR，其高尔基细胞表面转运和分选 由泛素化、类似泛素化的翻译后修饰和三个相互作用的 蛋白质、C1orf27(内质网膜蛋白)、螺旋α-螺旋杆蛋白1和高尔基体定位的γ 耳朵含ARF结合蛋白3(GGA3)。我们将定义蛋白质超甲基化的新功能，并 C1orf27在内质网-高尔基体运输和分选中，以及HCR1和GGA3在高尔基体后交通和 对α2A-AR和α2B-AR进行分类，并阐明其作用机制。拟议的研究是一项 继续我们研究GPCRs顺行贩运的长期努力，这导致了 一些结构决定因素和调节蛋白的发现对gpr的出口和 分类。一如既往，我们将采用最先进的生化、免疫化学和活细胞成像技术 剖析沿生物合成途径运输GPCR的机械方面的技术，包括 成熟、分类和定向。这些研究将为gpcr的调控提供重要的见解。 出口贩运，在GPCR超家族的研究中是一个很少探索的领域。