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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 端规则通路

基本信息

批准号：
10202561
负责人：
ALEXANDER J VARSHAVSKY
金额：
$ 59.57万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202561
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 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

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 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.

项目总结/文摘