PROTEOLYTIC SIGNALING BY POLYUBIQUITIN CHAINS

描述：泛素-蛋白酶体途径是主要机制 真核细胞中短寿命蛋白质的周转。的作用 泛素在蛋白质水解中是一种信号;泛素化赋予 蛋白酶体的底物识别。在这条道路上，校长 信号是通过Lys 48-Gly 76异肽键连接的多聚泛素链 在连续的泛素之间。这条链条与 蛋白酶体识别因子最终决定了蛋白酶体的稳定性。 大部分细胞内蛋白质。校长以前的工作 研究人员和其他人已经表明，将泛素组装成这样的一个 链增强了泛素蛋白水解信号的识别，但 对这种效应的分子基础知之甚少。在这一提议中， 首席研究员将寻求详细了解 多聚泛素信号的识别。这一目标将通过 描述了链的分子特征，这些特征对于 通过鉴定和表征新的蛋白酶体， 负责识别链的组件， 对纯化的蛋白酶体进行机理研究，以阐明 多聚泛素信号识别与底物的偶联 周转研究将验证新的假设，即组装泛素 Lys 48连接的链产生三维信号， 由26 S监管模型中的特定因素识别 蛋白酶体。除了蛋白酶体的靶向底物外， 可能预示着另一种命运细胞的能力，以区分 泛素化蛋白质的几种潜在命运 要求存在有选择地承认 这些物种，但这些机制仍有待确定。的发现 多聚泛蛋白提出了交替连接的可能性 多聚泛素链用于使多聚泛素的信号传导功能多样化， 泛素。这一假设将在拟议的研究中处理 通过分析多聚泛素链的结构和识别， 通过Lys 63连接。

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.