PROTEOLYTIC SIGNALING BY POLYUBIQUITIN CHAINS

描述：泛素-蛋白酶体途径是主要的机制。 真核细胞中短寿命蛋白质的周转。的作用 泛素在蛋白质降解中是一种信号；泛素化赋予 蛋白酶体对底物的识别。在这条道路上，主体 Signal是由Lys48-Gly76异肽键连接的多泛素链 在连续的泛素之间。这条链条与 蛋白酶体识别因素最终决定了一种 很大一部分细胞内蛋白质。校长之前的工作 研究人员和其他人已经表明，将泛素组装成这样一种 Chain增强了泛素蛋白分解信号的识别，但 这种效应的分子基础还知之甚少。在这份提案中， 首席调查员将寻求对 多泛素信号的识别。这一目标将通过以下方式实现 描绘了链的分子特征，这些分子特征对 它的识别，通过鉴定和表征新的蛋白酶体 负责识别链的组件，并通过 对纯化的蛋白酶体进行机制研究，以阐明 多泛素信号识别与底物的耦合 营业额。研究将检验组装泛素这一新假说 进入Lys48连接链，产生了一个三维信号 由26S监管模式内的特定因素认可 蛋白酶体。除了将底物定位于蛋白酶体外，泛素化 可以预示另一种命运。细胞区分不同物种的能力 泛素化蛋白质潜在可用的几种命运 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。发现了 多泛素增加了交替连接的可能性 多泛素链的作用是使信号转导功能多样化。 泛素。这一假设将在拟议的研究中得到处理。 通过对多泛素链的结构分析和识别 它们通过Lys63连接在一起。

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.