The N-end Rule Pathway and Ubr1 enforce protein compartmentalization via P2-encoded cellular location signals

The Arg/N-end Rule Pathway and Ubr1, an E3 ligase conserved from yeast to humans, is involved in the degradation of misfolded proteins in the cytosol. However, the root physiological purpose of this activity is not completely understood. Through a systematic examination of single residue P2-position mutants of misfolded proteins, and global and targeted bioinformatic analyses of the yeast proteome, we determined that Ubr1 preferentially targets mistranslocated secretory and mitochondrial proteins in the cytosol. Degradation by Ubr1 is dependent on the recognition of cellular location signals that are naturally embedded into the 2nd amino acid residue of most proteins. This P2-encoded location signaling mechanism may shed light on how Ubr1 and the N-end rule pathway are involved in neurodegenerative diseases such as Alzheimer's and Parkinson's. A corollary to this discovery is that the N-end rule pathway enforces the compartmentalization of secretory and mitochondrial proteins by degradi...

精氨酸/N端规则通路（Arg/N-end Rule Pathway）与从酵母到人类均保守的E3泛素连接酶（E3 ligase）Ubr1，共同参与细胞质基质中错误折叠蛋白质的降解过程。然而，该活性的根本生理功能尚未完全阐明。我们通过对错误折叠蛋白质的单残基P2位突变体开展系统性筛查，并针对酵母蛋白质组（proteome）进行全局与靶向生物信息学分析，证实Ubr1可优先靶向细胞质基质中转运错误的分泌蛋白与线粒体蛋白。Ubr1介导的降解依赖于对细胞定位信号的识别，此类信号天然嵌入绝大多数蛋白质的第2位氨基酸残基中。这种由P2位编码的定位信号机制，或可为阐释Ubr1及N端规则通路如何参与阿尔茨海默病（Alzheimer's）、帕金森病（Parkinson's）等神经退行性疾病提供全新视角。本发现的一项推论为，N端规则通路可通过降解（原文此处截断为degradi...）实现分泌蛋白与线粒体蛋白的区域化隔离。