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

酵母和哺乳动物中的 GID 泛素连接酶和 Pro/N 端规则途径

• 批准号: 9378044
• 负责人: ALEXANDER J VARSHAVSKY
• 金额: $ 61.77万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378044
• 关键词: Acetylesterase; Address; Adult; Apoptosis; Autophagocytosis; Bacteria; Biochemical Genetics; Biological; Biological Process; Biology; Blood Pressure; Brain; Cardiovascular system; Chemicals; Chromosome Cohesion; DNA; Defect; Development; Disease; Eukaryota; G-substrate; GTP-Binding Proteins; Genetic Transcription; Glucose; Grant; Health; Heme; Human; Immunity; Infection; Laboratories; Lead; Ligands; Ligase; Malignant Neoplasms; Mammals; Mediating; Medical; Meiosis; Microfilaments; Mouse Strains; Mus; Muscle; N-terminal; Nerve Degeneration; Nitric Oxide; Organ; Oxygen; Pancreas; Pathway interactions; Peptide Hydrolases; Peptides; Physiological; Plant Leaves; Plants; Play; Process; Proline; Proteins; Proteolysis; Regulation; Repression; Research; Role; Saccharomyces cerevisiae; Signal Transduction; Site; Specificity; Spermatogenesis; Starvation; Syndrome; System; Testis; Ubiquitin; Update; Ursidae Family; Work; Yeasts; cell motility; design; human disease; insight; lipid metabolism; misfolded protein; multicatalytic endopeptidase complex; neurogenesis; novel; protein complex; protein degradation; recognins; repaired; segregation; stem; stoichiometry; ubiquitin ligase; ubiquitin-protein ligase

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.

项目摘要/摘要 泛素 - 蛋白酶体系统（泛素系统）调节的蛋白水解在 多种生物学过程，对人类健康和疾病有重大影响，包括 从癌症和神经退行性变化到心血管综合征的疾病 免疫。我们对泛素 - 蛋白酶体系统和泛素依赖性的N端规则途径的研究 在过去的三十年中 目前正在获得支持的第31年。 N端规则途径识别含有N末端的蛋白质 降解信号称为n-脱果龙，polyupiquityLeS trices prits这些蛋白质，从而导致它们 蛋白酶体降解。 n端规则途径的识别成分称为n-识别剂。 在真核生物中，n-识别素是可以靶向N-脱绿素的E3泛素连接酶。真核生物N端规则 途径由三个分支组成。第一个分支称为arg/n-end规则途径，针对特定 蛋白质底物的非乙酰化N末端残基。这个分支，由我们的实验室发现，1986年， 仍然是生物学见解的源泉。第二个分支称为AC/N-END规则途径，是 我们的实验室在2010年发现。该途径识别含有N末端乙酰化的蛋白质 残留物。 N-End规则途径的第三个分支称为Pro/N-End规则途径，已经出现 通过未发表的研究，在过去的两年中，我们的实验室。这种蛋白水解途径是 由先前已知的泛素连接酶介导的，称为GID并识别N末端脯氨酸（Pro） 蛋白质的残基和相邻的序列基序。 目前（DK039520）续订申请侧重于这些（最新）的进步，并且很大程度上 在酵母和哺乳动物中均未探索的Pro/N-End规则途径。它的生物功能包括 调节在需要从头综合的细胞状态之间生理上重要的过渡 葡萄糖（例如，饥饿或半饥饿状态）和充足的葡萄糖可用性条件。这 Pro/n-End规则途径也具有其他功能，这些功能已开始出现 最近鉴定出由Pro/N-End靶向或相互作用的非葡萄糖蛋白 在酵母和哺乳动物中，统治途径。这些以及相关的酵母和哺乳动物研究 当前续签应用的具体目的，将提高对蛋白质降解的理解和 普遍呈现的n端规则途径。