New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways

项目总结/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-降解决定子通路的研究 （以前称为“N端规则途径”）在三十多年的时间里， 在一定程度上，目前的赠款（DK 039520），目前在其第34年的支持。N-降解决定子途径 识别含有N-末端（Nt）降解信号的蛋白质，称为N-降解决定子， 蛋白质，从而导致其降解的蛋白酶体或自噬。承认的组成部分 N-降解决定子途径，称为N-识别蛋白，是可以靶向N-降解决定子的E3泛素连接酶。一种真核 N-降解决定子途径，称为Arg/N-降解决定子途径，特别是靶向特定的未修饰的NT-残基 蛋白质底物。另一个NT蛋白水解系统，称为Pro/N-degron途径，识别， 特别是蛋白质底物的N t-脯氨酸（Pro）残基。 本DK 039520更新申请源于我们过去2年未发表的研究， 关注酵母（S.酿酒酵母）Pro/N-degron和Arg/N-degron途径，包括 特异性氨肽酶和最近发现的Ubr 1，Arg/N-降解决定子途径的E3， 不仅针对N-degron，也针对C-degron。这些和相关的研究，在《联合国的具体目标》中有描述。 DK 039520的更新申请，将促进对蛋白质降解的理解， 普遍存在的（以及医学上显著的）N-降解决定子途径。

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 ubiquitin-dependent N-degron pathways (previously called “N-end rule pathways”) over more than three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 34th year of support. N-degron pathways recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues of protein substrates. Another Nt-proteolytic system, called the Pro/N-degron pathway, recognizes, in particular, the Nt-proline (Pro) residue of protein substrates. This DK039520 renewal application stems from our unpublished studies over the last ~2 years, and focuses on the yeast (S. cerevisiae) Pro/N-degron and Arg/N-degron pathways, including the functions of specific aminopeptidases and the recently discovered ability of Ubr1, the E3 of the Arg/N-degron pathway, to target not only N-degrons but also C-degrons. These and related studies, described in Specific Aims of the DK039520 renewal application, will advance the understanding of protein degradation and the universally present (as well as medically significant) N-degron pathways.