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

Pro/N Degron 和 Arg/N-Degron 途径的新机制和功能

基本信息

批准号：
10596188
负责人：
ALEXANDER J VARSHAVSKY
金额：
$ 59.9万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-02-11 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596188
关键词：
Acetylation Amino Acids Aminopeptidase Animals Apoptosis Autophagocytosis Biological Process Biology C-terminal Calpain Cardiovascular system Caspase Cathepsins Cell Cycle Cell Differentiation process Cell Nucleus Cells Chromosome Cohesion Circadian Rhythms Cytoskeletal Proteins Cytosol DNA Repair Defect Disease Enzymes Eukaryotic Cell GTP-Binding Proteins Genes Genetic Code Genetic Transcription Gluconeogenesis Grant Health Heme Human Immune system Immunity Infection Inflammation Laboratories Length Link Malignant Neoplasms Mammals Mediating Medical Meiosis Mitotic Checkpoint Molecular Chaperones N-terminal Names Natural Immunity Nerve Degeneration Nitric Oxide Oxygen Pathway interactions Peptide Hydrolases Peptide Transport Phosphotransferases Physiological Plants Play Process Progress Reports Proline Proteins Proteolysis Regulation Research Role Route Saccharomyces cerevisiae Semantics Signal Transduction Spermatogenesis Syndrome System Terminology Transcriptional Regulation Translations Ubiquitin Work Yeasts adaptive immunity biological adaptation to stress cell motility deamidation fungus glutamyl aminopeptidase human disease in vivo lipid metabolism misfolded protein multicatalytic endopeptidase complex neurogenesis oxidation protein complex protein degradation recognins segregation separase stem stoichiometry ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

项目概要/摘要泛素-蛋白酶体系统（泛素系统）调节的蛋白水解作用在多种生物过程，对人类健康和疾病具有重大影响，包括疾病范围从癌症和神经退行性疾病到心血管综合征和缺陷我们对泛素-蛋白酶体系统和泛素依赖性 N-降解决定子途径的研究。（以前称为“N 端规则路径”）经过三十多年的发展，在很大程度上成为可能在某种程度上，通过目前的资助（DK039520），目前正处于 N-degron 途径的第 34 年支持。识别含有 N 末端 (Nt) 降解信号（称为 N 降解决定子）的蛋白质，对这些蛋白质进行多泛素化蛋白质，从而导致其被蛋白酶体或自噬的识别成分降解。 N-降解决定子途径称为 N-识别蛋白，是一种可以靶向 N-降解决定子的 E3 泛素连接酶。 N-degron 途径，称为 Arg/N-degron 途径，特别针对特定的未修饰 Nt 残基另一种 Nt 蛋白水解系统，称为 Pro/N-degron 途径，可识别蛋白质底物。特别是蛋白质底物的 Nt-脯氨酸 (Pro) 残基。此 DK039520 续订申请源自我们过去约 2 年未发表的研究，并且重点关注酵母 (S. cerevisiae) Pro/N-degron 和 Arg/N-degron 途径，包括以下功能特定的氨肽酶和最近发现的 Ubr1（Arg/N-degron 途径的 E3）的能力，不仅针对 N-降解决定子，还针对 C-降解决定子这些及相关研究，如具体目标中所述。 DK039520 更新应用程序，将增进对蛋白质降解和普遍存在的（以及具有医学意义的）N-降解决定子途径。