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.

总结 G蛋白偶联受体（GOCR）调节多种细胞功能，并且是免疫调节的重要靶点。 治疗学研究GPCR的一个基本但知之甚少的问题是如何靶向GPCR 贩运已经实现。我们研究计划的总体目标是阐明 目的地的新生GPCR靶向其功能目的地，并了解靶向在 调节细胞对激素和药物的反应。在这一广泛目标下，该提案将使用α2- 肾上腺素能受体（α2-AR）作为模型，以解决以下两个问题， 了解GPCR顺行运输：1）新合成的GPCR如何从 内质网（ER），然后运输途中从ER通过高尔基体的细胞表面; 以及2）在GPCR期间GPCR如何彼此分选以及如何从非GPCR质膜蛋白分选 它们的运输沿着生物合成途径。这个项目的前提是我们最近的发现，ER- 高尔基体细胞表面α2A-AR和α2B-AR的转运和分选，两种密切相关的原型GPCR， 由ufmylation（一种类似于遍在化的翻译后修饰）和三种相互作用协调 蛋白质，C1 orf 27（ER膜蛋白），卷曲螺旋α-螺旋杆蛋白1（HCR 1）和高尔基体定位的γ 含耳的ARF结合蛋白3（GGA 3）。我们将定义蛋白质去甲酰基化的新功能， C1 orf 27在ER-高尔基体运输和排序中，以及HCR 1和GGA 3在后高尔基体运输和排序中 对α2A-AR和α2B-AR进行分类，并阐明其作用机制。拟议的研究是一个 继续我们长期以来的努力，研究GPCR的顺行贩运，这导致 发现了一些对GPCR输出至关重要的结构决定因素和调节蛋白， 分类和过去一样，我们将采用最先进的生物化学、免疫化学和活细胞成像技术 分析气相化学还原沿着生物合成途径运输的机制方面的技术，包括 成熟、分选和靶向。这些研究将为GPCR的调控提供重要的见解 出口贩运是GPCR超家族研究中探索较少的领域。