The GID Ubiquitin Ligase and the Pro/N-End Rule Pathway in Yeast and Mammals

项目概要/摘要 由泛素-蛋白酶体系统（泛素系统）调节的蛋白质水解在以下方面起重要作用： 许多生物过程，并对人类健康和疾病产生重大影响，包括 从癌症和神经退行性疾病到心血管综合征和心脏缺陷， 免疫力我们对泛素-蛋白酶体系统和泛素依赖的N-末端规则途径的研究 在过去的三十年里，在很大程度上，通过目前的赠款（DK 039520 - 30）， 目前已进入第31个年头。N-末端规则途径识别含有N-末端的蛋白质。 降解信号称为N-降解决定子，多聚泛素化这些蛋白质，从而导致它们的 通过蛋白酶体降解。N端规则途径的识别组分被称为N-识别蛋白。 在真核生物中，N-识别蛋白是可以靶向N-降解决定子的E3泛素连接酶。真核生物的N-末端规则 路径由三个分支组成。第一个分支称为Arg/N-末端规则途径，靶向特定的 蛋白质底物的未乙酰化的N-末端残基。这个分支是我们实验室在1986年发现的， 仍然是生物学见解的源泉。第二个分支称为Ac/N末端规则途径， 在2010年被我们的实验室发现。该途径识别带有N-末端乙酰化的蛋白质， 残基N端规则途径的第三个分支，称为Pro/N端规则途径，已经出现 通过我们实验室在过去的两年里未发表的研究。这种蛋白水解途径是 由以前已知的称为GID的泛素连接酶介导，并识别N-末端脯氨酸（Pro） 蛋白质的残基和邻接的序列基序。 目前（DK039520）的更新申请侧重于这些（最新）进展， 未探索的Pro/N-末端规则途径，在酵母和哺乳动物中。其生物学功能包括： 调节生理上重要的细胞状态之间的转换，需要从头合成 葡萄糖（例如，饥饿或半饥饿状态）和充足葡萄糖可用性的条件。的 Pro/N-end规则途径也有其他功能，这些功能正在开始出现，部分是通过我们的 最近鉴定出了由Pro/N-末端靶向或与Pro/N-末端相互作用的非致突变蛋白质 在酵母和哺乳动物中都是规则途径。这些和相关的酵母和哺乳动物研究，描述在 本更新申请的具体目的将促进对蛋白质降解的理解， 普遍存在的N端规则路径。

Project Summary/Abstract Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes and has major ramifications for human health and disease, including illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of immunity. Our studies of the ubiquitin-proteasome system and the ubiquitin-dependent N-end rule pathway over the last three decades were made possible, to a large extent, by the present grant (DK039520-30), currently in its 31st year of support. The N-end rule pathway recognizes proteins containing N-terminal degradation signals called N-degrons, polyubiquitylates these proteins and thereby causes their degradation by the proteasome. Recognition components of the N-end rule pathway are called N-recognins. In eukaryotes, N-recognins are E3 ubiquitin ligases that can target N-degrons. The eukaryotic N-end rule pathway consists of three branches. The first branch, called the Arg/N-end rule pathway, targets specific unacetylated N-terminal residues of protein substrates. This branch, discovered by our laboratory in 1986, continues to be a fount of biological insights. The second branch, called the Ac/N-end rule pathway, was discovered by our laboratory in 2010. This pathway recognizes proteins that bear N-terminally acetylated residues. The third branch of the N-end rule pathway, termed the Pro/N-end rule pathway, has emerged through unpublished studies, over the last two years, by our laboratory. This proteolytic pathway is mediated by the previously known ubiquitin ligase called GID and recognizes the N-terminal proline (Pro) residue of a protein and an adjoining sequence motif. The present (DK039520) renewal application focuses on these (latest) advances and the largely unexplored Pro/N-end rule pathway, in both yeast and mammals. Its biological functions include the regulation of physiologically important transitions between cellular states that require de novo synthesis of glucose (for example, starvation or semi-starvation states) and conditions of ample glucose availability. The Pro/N-end rule pathway has other functions as well, which are beginning to emerge, in part through our recent identification of non-gluconeogenic proteins that are either targeted by or interact with the Pro/N-end rule pathway, in both yeast and mammals. These and related yeast and mammalian studies, described in Specific Aims of the present renewal application, will advance the understanding of protein degradation and the universally present N-end rule pathway.