The central role of the PACS family of proteins in cellular organization

PACS 蛋白家族在细胞组织中的核心作用

• 批准号: RGPIN-2019-04094
• 负责人: Dikeakos, DimitriosJimmy
• 金额: $ 3.06万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714628
• 关键词: central; role; PACS; family; proteins

Background The movement of many proteins within cells is ensured by the membrane trafficking machinery. This machinery enables the correct subcellular localization of proteins which guarantees proteins fulfill their cellular functions. Overall, membrane trafficking maintains cellular homeostasis. This proposal is centered on the membrane trafficking regulator proteins Phosphofurin Acid Cluster Sorting (PACS) 1 and 2. The PACS proteins form key interactions with multiple cellular proteins termed cargo and shuttle the latter cargo to the correct subcellular location. The importance and diversity of PACS-1 and PACS-2 trafficking events demonstrates the central role these proteins play in trafficking. Indeed, PACS-1 trafficking is implicated in the formation of primary cilia, the delivery of activating molecules to specific cellular compartments and the conversion of inactive precursor proteins to active proteins, amongst other functions. Conversely, PACS-2 trafficking events can function during key cellular events such as maintaining cellular calcium levels and modulating cellular death pathways. Hypothesis We hypothesize that PACS proteins are central organizers of the cell by orchestrating multiple protein-protein interactions to enable trafficking of itinerant cargo to precise subcellular locales. Proper trafficking of proteins is critical for them to subsequently perform their functions. We further hypothesize that defining how novel PACS:protein interactions function will shed significant insight into defining the central role of PACS proteins in cellular organization. Progress My laboratory has identified a novel trafficking pathway that is controlled by PACS-1. This pathway is implicated in the delivery of hormones to a specific subcellular location, the dense core secretory granule. In addition, my laboratory has defined the full range of PACS-1 & PACS-2 interacting partners which has revealed an unexpected concentration of PACS roles in the nucleus. Overall, we will study these mechanisms aided by a variety of techniques that we have perfected and developed during the previous funding period. Aims Elucidating the roles of PACS-1 & PACS-2 in multiple membrane trafficking pathways is the overarching aim of this research program. Aim1: Defining the role of PACS-1 in the sorting of cargo to dense core secretory granules. Aim 2: Defining the role of PACS-1 in the secretion of cargo from the dense core secretory granule. Aim 3: Defining the protein-protein interactions and roles of PACS-1 and PAC-2 in the nucleus Significance This discovery-based research program will address important and unique questions concerning the pathways that are governed by the central membrane trafficking regulator PACS proteins. Our long-term plans are centered on exploring the full range of PACS-1 and PACS-2 cargo that we have discovered during the previous funding period.

背景 许多蛋白质在细胞内的运动是由膜运输机制保证的。这种机制使蛋白质能够正确地亚细胞定位，从而保证蛋白质实现其细胞功能。总体而言，膜运输维持细胞内稳态。该建议集中在膜运输调节蛋白磷酸弗林酸簇分选（PACS）1和2。PACS蛋白与称为货物的多种细胞蛋白形成关键相互作用，并将后者货物运送到正确的亚细胞位置。PACS-1和PACS-2运输事件的重要性和多样性表明了这些蛋白质在运输中发挥的核心作用。事实上，PACS-1运输涉及初级纤毛的形成、活化分子向特定细胞区室的递送以及非活性前体蛋白向活性蛋白的转化等功能。相反，PACS-2运输事件可以在关键细胞事件期间起作用，例如维持细胞钙水平和调节细胞死亡途径。 假设 我们假设PACS蛋白是细胞的中心组织者，通过协调多种蛋白质-蛋白质相互作用，使流动货物能够运输到精确的亚细胞区域。蛋白质的适当运输对于它们随后执行其功能至关重要。我们进一步假设，定义新的PACS：蛋白质相互作用的功能将揭示重要的见解，定义PACS蛋白质在细胞组织中的核心作用。 进展 我的实验室已经确定了一种由PACS-1控制的新型贩运途径。这一途径涉及将激素递送到特定的亚细胞位置，即致密的核心分泌颗粒。此外，我的实验室已经定义了PACS-1和PACS-2相互作用的伙伴的全部范围，这揭示了PACS作用在细胞核中的意想不到的集中。总的来说，我们将研究这些机制，并辅之以我们在上一个资助期内完善和开发的各种技术。 旨在 阐明PACS-1和PACS-2在多个膜运输途径中的作用是本研究计划的首要目标。 目的1：确定PACS-1在将货物分选为致密核心分泌颗粒中的作用。 目的2：明确PACS-1在致密核心分泌颗粒分泌货物中的作用。 目的3：确定PACS-1和PAC-2在细胞核中的蛋白质-蛋白质相互作用和作用 意义 这项基于发现的研究计划将解决有关由中央膜运输调节剂PACS蛋白管理的途径的重要和独特的问题。我们的长期计划集中在探索我们在上一个资助期发现的PACS-1和PACS-2货物的全方位。