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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.

用化学方法解码非典型的多聚泛素链泛素系统对于调节细胞和生物体的多种功能至关重要对人类健康至关重要。虽然我们对泛素系统的认识最初源于通过对蛋白酶体介导的蛋白质降解的研究，已经清楚的是，对于许多非蛋白水解功能是不可或缺的。许多非典型的泛素链与除了蛋白质降解之外的细胞功能。K63连接的多聚泛素链与DNA损伤耐受已经发现是真核无错误损伤旁路的信号。然而，很少有人知道这是如何做到的。信号调节DNA损伤耐受途径。解码K63的下游蛋白质- PCNA上的多聚泛素信号仍然需要鉴定。为了破译不同的细胞角色，多聚泛素化，产生多聚泛素化蛋白质和非典型泛素的化学方法需要具有限定结构和长度的链。这将导致下游读者的发现蛋白质在DNA损伤耐受性和其他重要的细胞过程。它还将使深入生物化学和生物物理特性的非典型的多聚泛素链的识别，阅读器蛋白。这将扩大我们对许多生物过程的理解，泛素化，并提供新的途径和目标，适合治疗干预。