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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688555
• 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。这一机制使蛋白质能够正确的亚细胞定位，从而确保蛋白质履行其细胞功能。总体而言，膜转运维持了细胞内环境的稳定。该建议以膜转运调节蛋白磷酸尿酸簇排序(PACS)1和2为中心。PACS蛋白与多个细胞蛋白形成关键相互作用，称为Cargo，并将后者运送到正确的亚细胞位置。PACS-1和PACS-2贩运事件的重要性和多样性表明了这些蛋白质在贩运中发挥的核心作用。事实上，PACS-1的运输与初级纤毛的形成、将激活分子输送到特定的细胞隔间以及将非活性前体蛋白转化为活性蛋白等功能有关。相反，PACS-2转运事件可以在关键的细胞事件中发挥作用，如维持细胞钙水平和调节细胞死亡途径。*假设*我们假设PACS蛋白是细胞的中央组织者，通过协调多个蛋白质-蛋白质相互作用，使巡回货物能够运输到精确的亚细胞位置。蛋白质的适当运输对它们随后履行其功能至关重要。我们进一步假设，定义新的PACS：蛋白质相互作用的功能将为定义PACS蛋白质在细胞组织中的中心作用提供重要的见解。*进展*我的实验室已经发现了一条由PACS-1控制的新的运输途径。这一途径涉及将激素输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相互作用的全部伙伴范围，这揭示了PACS在细胞核中出人意料的集中作用。总的来说，我们将借助我们在前一个资助期间完善和开发的各种技术来研究这些机制。*目的*阐明PACS-1和PACS-2在多条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在将货物分选到致密的核心分泌颗粒中的作用。*目标2：确定PACS-1在从致密的核心分泌颗粒分泌货物中的作用。*目标3：确定蛋白质-蛋白质相互作用和作用。PACS-1和PAC-2在细胞核中的作用*意义*这一基于发现的研究计划将解决与中央膜运输调节因子PACS蛋白有关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金期间发现的PACS-1和PACS-2货物的全系列。**