PROTEOLYTIC SIGNALING BY POLYUBIQUITIN CHAINS

多聚泛素链的蛋白水解信号传导

• 批准号: 2905576
• 负责人: Cecile M. Pickart
• 金额: $ 22.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905576
• 关键词: biological signal transduction; chemical aggregate; chemical binding; chemical chain length; chemical conjugate; chemical kinetics; crosslink; crystallization; denaturing gradient gel electrophoresis; endopeptidases; enzyme activity; enzyme mechanism; enzyme model; enzyme structure; enzyme substrate; hydropathy; intermolecular interaction; proteasome; protein degradation; ubiquitin; western blottings

DESCRIPTION: The ubiquitin-proteasome pathway is the predominant mechanism for the turnover of short-lived proteins in eukaryotic cells. The role of ubiquitin in proteolysis is that of a signal; ubiquitination confers substrate recognition by the proteasome. In this pathway, the principal signal is a polyubiquitin chain linked by Lys48-Gly76 isopeptide bonds between successive ubiquitins. The interaction of this chain with proteasomal recognition factors ultimately determines the stability of a large fraction of intracellular proteins. Previous work by the principal investigator and others has shown that assembling ubiquitin into such a chain potentiates the recognition of the ubiquitin proteolytic signal, but the molecular basis of this effect is poorly understood. In this proposal, the principal investigator will seek a detailed understanding of the recognition of polyubiquitin signal. This goal will be achieved by delineating the molecular features of the chain which are important for its recognition, by identifying and characterizing novel proteasomal components which are responsible for recognizing the chain, and by conducting mechanistic studies of purified proteasomes, so as to elucidate the coupling between polyubiquitin signal recognition and substrate turnover. Studies will test the novel hypothesis that assembling ubiquitin into a Lys48-linked chain creates a three dimensional signal that is recognized by specific factors within the regulatory model of the 26S proteasome. Besides targeting substrates to the proteasome, ubiquitination can signal alternate fate. The ability of the cell to distinguish among several fates that are potentially available to ubiquitinated proteins requires that there exist mechanisms for the selective recognition of these species, but these mechanisms remain to be defined. The discovery of polyubiquitin raises the possibility that alternatively-linked polyubiquitin chains serve to diversify the signaling functions of ubiquitin. This hypothesis will be treated in the proposed research through analysis of the structure and recognition of polyubiquitin chains that are linked through Lys63.

描述：泛素 - 蛋白酶体途径是主要机制 用于真核细胞中短寿命蛋白的营业额。的作用 蛋白水解中的泛素是信号的。泛素化 蛋白酶体的底物识别。在这条路中，校长 信号是由Lys48-Gly76 Isophide键连接的多泛素链 在连续的泛素之间。该链的相互作用与 蛋白酶体识别因素最终决定了 大部分细胞内蛋白。校长的先前工作 研究者和其他人表明，将泛素组装成这样的 链增强了对泛素蛋白水解信号的识别，但 这种作用的分子基础知之甚少。在此提案中， 首席研究人员将寻求对 识别多泛素信号。这个目标将通过 描述链的分子特征，这对于 通过识别和表征新颖的蛋白酶体的识别 负责识别链的组成部分以及 进行纯化蛋白酶体的机械研究，以阐明 多泛素信号识别与底物之间的耦合 周转。研究将检验组装泛素的新假设 进入lys48连锁链中会产生一个三维信号 在26S的调节模型中被特定因素认可 蛋白酶体。除了将底物靶向蛋白酶体，泛素化 可以发出替代命运的信号。细胞区分区分的能力 几种可能可用于泛素化蛋白的命运 要求存在选择性识别的机制 这些物种，但这些机制仍有待定义。发现 多泛素增加了互联的可能性 多泛素链用于多元化的信号传导功能 泛素。该假设将在拟议的研究中得到处理 通过分析多泛素链的结构和识别 通过Lys63链接。