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Decoding the non-canonical polyubiquitin chains using chemical approaches

使用化学方法解码非规范多聚泛素链

基本信息

批准号：
10364631
负责人：
Zhihao Zhuang
金额：
$ 30.32万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364631
关键词：
ATP phosphohydrolase Affinity Binding Binding Proteins Biochemical Bioinformatics Biological Assay Biological Process Biotin Bypass Cell physiology Cells Chemicals Complex Crosslinker Cryoelectron Microscopy Cyclooctenes DNA DNA Binding DNA Damage DNA biosynthesis DNA replication fork Data Development Eukaryota Event Generations Goals Health Homologous Gene Human Individual Investigation Knowledge Label Length Lesion Ligation Link Lysine Mass Spectrum Analysis Mediating Methods Modeling Modification Orthologous Gene Pathway interactions Polyubiquitin Polyubiquitination Proteins Reader Regulation Resistance Role Signal Transduction Streptavidin Structure System Technology Testing Therapeutic Intervention UV induced Ubiquitin Ubiquitination Yeasts biophysical properties crosslink multicatalytic endopeptidase complex mutant novel novel therapeutic intervention protein degradation reconstitution recruit response stem thioether

项目摘要

Decoding the noncanonical polyubiquitin chains using chemical approaches The ubiquitin system is crucial for the regulation of a wide range of cellular and organismal functions essential for the human health. Although our knowledge of the ubiquitin system initially stems from the investigation into proteasome-mediated protein degradation, it has become clear that ubiquitination is also indispensible for many non-proteolytic functions. Many noncanonical ubiquitin chains are associated with cellular functions other than protein degradation. The K63-linked polyubiquitin chain in DNA damage tolerance has been found to be signal for the eukaryotic error-free lesion bypass. However, little is known as to how this signal regulates the DNA damage tolerance pathways. The downstream proteins that decode the K63- polyubiquitin signals on PCNA still need to be identified. In order to decipher the diverse cellular roles of polyubiquitination, chemical approaches of generating polyubiquitinated proteins and noncanonical ubiquitin chains with defined structure and length are needed. This will lead to the discovery of the downstream reader proteins in DNA damage tolerance and other important cellular processes. It will also enable in-depth biochemical and biophysical characterizations of the recognition of noncanonical polyubiquitin chains by the reader proteins. This will broaden our understanding of the many biological processes regulated by ubiquitination and furnish new pathways and targets amenable for therapeutic intervention.

用化学方法破译非正则多泛素链泛素系统对于调节广泛的细胞和组织功能至关重要。对人类健康至关重要。尽管我们对泛素系统的了解最初源于对蛋白酶体介导的蛋白质降解的研究表明，泛素化也是是许多非蛋白分解功能不可缺少的。许多非正则泛素链与蛋白质降解以外的细胞功能。K63连接的多泛素链在DNA损伤耐受中的作用已被发现是真核细胞无错误损伤搭桥的信号。然而，人们对这一点知之甚少信号调节DNA损伤耐受途径。破译K63的下游蛋白质- 增殖细胞核抗原上的多泛素信号仍有待鉴定。为了破译不同的细胞角色多泛素化、产生多泛素化蛋白的化学方法和非正则泛素需要具有定义的结构和长度的链条。这将导致发现下游阅读器蛋白质在DNA损伤耐受性和其他重要的细胞过程中。它还将使深入的识别非正则多泛素链的生化和生物物理特征阅读器蛋白。这将扩大我们对许多生物过程的理解，这些过程由泛素化，并为治疗干预提供新的途径和靶点。