Mechanistic Analysis of the Ubiquitin-Proteasome System

泛素-蛋白酶体系统的机理分析

• 批准号: 10622200
• 负责人: RANDALL W KING
• 金额: $ 45.77万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622200
• 关键词: Biological; Biology; Cell Survival; Cell division; Cell physiology; Cells; Disease; Enzymes; Excision; Genome; Goals; Health; Human; Knowledge; Malignant Neoplasms; Methods; Modernization; Modification; Molecular Target; Mutation; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Proteomics; Regulation; Regulatory Pathway; Research; Role; Signal Transduction; Specificity; Substrate Specificity; System; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; drug development; enzyme substrate; experimental study; insight; interest; multicatalytic endopeptidase complex; new therapeutic target; programs; protein protein interaction; ubiquitin ligase; virtual

Project Summary / Abstract The ubiquitin-proteasome system (UPS) regulates the activity, localization and stability of thousands of proteins in the cell. By catalyzing the covalent attachment or removal of ubiquitin to target proteins, the enzymes of the UPS regulate virtually every cellular process, including cell signaling, cell survival and cell division. The widespread influence of the UPS on biology also has important consequences for human health, as mutations in components of the UPS cause diseases such as cancer. Encouragingly, the vast number of enzymes and protein-protein interactions in the UPS are also providing new drug targets to treat disease. There is growing interest in developing drugs that either inhibit the UPS or harness its ability to eliminate harmful proteins. For these reasons, mechanistic studies of the UPS have the potential to reveal new insights into biological regulation and may also help us understand mechanisms of disease pathogenesis and reveal opportunities for therapy. The focus of this proposal is to discover new substrates of the UPS and to characterize the specificity and regulation of enzymes that add and remove ubiquitin to these proteins. Although many components of the UPS are well-studied, we still have little insight into the molecular targets for hundreds of UPS enzymes encoded in the genome. This study will help fill this critical gap in our knowledge by identifying new enzyme-substrate relationships and providing new insights into how the enzymes of the system are regulated. It will apply modern quantitative proteomic methods to identify proteins that are modified by ubiquitin, and how these modifications change during cell division. This study will systematically examine the ability of deubiquitylating enzymes (DUBs) to remove ubiquitin from substrates, identifying new functional roles for these enzymes. The study will also examine the substrate specificity and regulation of specific ubiquitin conjugating enzymes and ubiquitin ligases, the proteins that conjugate ubiquitin to other proteins. Together, the experiments outlined in this study will identify new enzyme-substrate relationships in the UPS and provide new insights into how the UPS controls cell division. By defining these important regulatory pathways, the findings will provide a framework for understanding how these pathways are altered in cancer and may provide new targets for the development of drugs to treat disease.

项目总结/摘要 泛素-蛋白酶体系统（UPS）调节着成千上万种蛋白质的活性、定位和稳定性 得双曲余切值.通过催化泛素与靶蛋白的共价连接或去除， UPS几乎调节每个细胞过程，包括细胞信号传导、细胞存活和细胞分裂。的 UPS对生物学的广泛影响也对人类健康产生重要影响， 不间断电源的组成部分会导致癌症等疾病。令人鼓舞的是，大量的酶和 UPS中的蛋白质-蛋白质相互作用也为治疗疾病提供了新的药物靶点。人们越来越 他们对开发抑制UPS或利用其消除有害蛋白质的药物感兴趣。为 由于这些原因，UPS的机制研究有可能揭示生物调节的新见解 也可能帮助我们了解疾病的发病机制，并揭示治疗的机会。 该提案的重点是发现UPS的新底物，并表征其特异性和 调节添加和去除这些蛋白质的泛素的酶。虽然UPS的许多组件 虽然已经被充分研究，但我们仍然对编码在大肠杆菌中的数百种UPS酶的分子靶点知之甚少。 基因组这项研究将有助于填补这一关键空白，在我们的知识，确定新的酶底物 关系，并提供新的见解如何酶的系统进行调节。它将适用于现代 定量蛋白质组学方法来鉴定被泛素修饰的蛋白质，以及这些修饰是如何发生的。 细胞分裂时的变化。本研究将系统地研究去泛素化酶（DUBs） 从底物中去除泛素，确定这些酶的新功能作用。该研究还将 检查底物特异性和特异性泛素缀合酶和泛素连接酶的调节， 将泛素与其他蛋白质结合的蛋白质。总之，本研究中概述的实验将确定 新的酶-底物关系的UPS和UPS如何控制细胞分裂提供了新的见解。 通过定义这些重要的调节途径，这些发现将为理解如何 这些途径在癌症中发生改变，可能为开发治疗疾病的药物提供新的靶点。