The Mammalian Arg/N-End Rule Pathway: Substrates, Functions, and Mechanisms

哺乳动物 Arg/N 端规则途径：底物、功能和机制

• 批准号: 8601698
• 负责人: ALEXANDER J VARSHAVSKY
• 金额: $ 53.89万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-11 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601698
• 关键词: 26S proteasome; Address; Aminopeptidase; Apoptosis; BRCA1 gene; Biological; Biological Process; Biology; Calpain; Caspase; Defect; Down-Regulation; Doxycycline; Elastases; Eukaryota; Glutamine; Grant; Half-Life; Health; Human; Individual; Infection; Knock-in Mouse; Laboratories; Lead; Length; Life; Ligase; Malignant Neoplasms; Mammalian Cell; Mediating; Medical; Modification; Mus; Mutant Strains Mice; N-terminal; Nerve Degeneration; Pathway interactions; Peptide Hydrolases; Physiological; Play; Probability; Progress Reports; Protein Fragment; Protein Precursors; Proteinase 3; Proteins; Proteolysis; Publications; Puromycin; RIPK1 gene; Role; Signal Transduction; Syndrome; System; Targeted Research; Transferase; Ubiquitin; arginyllysine; aspartylglutamate; deamidation; human disease; in vivo; insight; leucyl-phenylalanine; multicatalytic endopeptidase complex; mutant; protein degradation; public health relevance; recognins; secretase; tryptophyltyrosine; ubiquitin ligase

DESCRIPTION (provided by applicant): 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. Our studies of the ubiquitin system and the N-end rule pathway over the last three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 27th year of support. This renewal application is about the N-end rule pathway of protein degradation. In eukaryotes, this pathway is a specific part of the ubiquitin system. The N-end rule relates the in vivo half-life of a protein to the identity of its -terminal residue. The N-end rule pathway of protein degradation consists of two distinct branches, the Ac/N-end rule pathway and the Arg/N-end rule pathway. The Ac/N-end rule pathway was discovered by our laboratory in 2010. It recognizes proteins with N-terminally acetylated residues. The Arg/N-end rule pathway, which targets specific unacetylated N-terminal residues, was discovered by our laboratory in 1986. This pathway continues to be a fount of biological insights and remains a major focus of our studies. The present (DK039520) renewal application is about the Arg/N-end rule pathway and the identification (as well as detailed studies) of new physiological Arg/N-rule substrates. Therefore the previous title of the DK039520 grant ("Ubiquitin Ligases, Mechanisms and Functions of the N-End Rule Pathway") was modified as follows in the present renewal application, to reflect its current emphasis: "The Mammalian Arg/N-End Rule Pathway: Substrates, Functions, and Mechanisms". The projects of this renewal application include functional and mechanistic studies of specific physiological substrates of the mammalian (mouse) Arg/N-end rule pathway, and the identification of new mammalian Arg/N-end rule substrates, including those that act as proapoptotic protein fragments, i.e., fragments whose formation during apoptosis (a specific kind of programmed cell death) increases the probability of apoptosis.

描述（由申请人提供）：由泛素-蛋白酶体系统（泛素系统）调节的蛋白水解在许多生物过程中起重要作用，并对人类健康产生重大影响。我们在过去三十年中对遍在蛋白系统和N端规则途径的研究在很大程度上得益于目前的资助（DK 039520），目前已进入第27年的支持。本次更新申请是关于蛋白质降解的N端规则途径。在真核生物中，该途径是泛素系统的特定部分。N-末端规则将蛋白质的体内半衰期与其N-末端残基的身份联系起来。蛋白质降解的N-末端规则途径由两个不同的分支组成，Ac/N-末端规则途径和Arg/N-末端规则途径。Ac/N-end规则途径是我们实验室在2010年发现的。它识别具有N-末端乙酰化残基的蛋白质。Arg/N-end rule pathway是本实验室于1986年发现的一种以特定的非乙酰化N-末端残基为靶点的分子。这一途径仍然是生物学见解的源泉，仍然是我们研究的主要焦点。目前（DK 039520）的更新申请是关于Arg/N-末端规则途径和新的生理Arg/N-规则底物的鉴定（以及详细研究）。因此，DK 039520授权的先前标题（“N-末端规则途径的泛素连接酶、机制和功能”）在本更新申请中修改如下，以反映其当前的重点：“哺乳动物Arg/N-末端规则途径：底物、功能和机制”。本次更新申请的项目包括哺乳动物（小鼠）Arg/N-末端规则途径的特定生理底物的功能和机制研究，以及新的哺乳动物Arg/N-末端规则底物的鉴定，包括作为促凋亡蛋白片段的那些，即，在细胞凋亡（一种特殊的程序性细胞死亡）过程中形成的片段增加了细胞凋亡的可能性。