Ubr1: A Protein Quality Control E3 Ubiquitin Ligase

Ubr1：蛋白质质量控​​制 E3 泛素连接酶

• 批准号: 8470658
• 负责人: Randolph Y. Hampton
• 金额: $ 27.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470658
• 关键词: Address; Age; Alzheimer' s Disease; Biochemical; Biological; Biological Assay; Categories; Cell physiology; Cells; Cellular Stress; Characteristics; Clinical; Collection; Dependence; Detection; Disease; Ensure; Etiology; Eukaryota; Genes; Genetic; Genetic Screening; Health; Human; Johanson-Blizzard syndrome; Learning; Length; Life; Ligase; Maintenance; Mammals; Mediating; Medical; Methods; Molecular Chaperones; Molecular Genetics; Mutagenesis; Mutation; Normal Cell; Organism; Paper; Parkinson Disease; Pathway interactions; Phenotype; Physiological; Process; Proteins; Publishing; Quality Control; RNA Interference; Role; Saccharomyces cerevisiae; Scanning; Societies; Stress; Testing; Ubiquitin-mediated Proteolysis Pathway; Ubiquitination; Work; base; gene interaction; genetic analysis; improved; in vivo; mutant; novel; protein misfolding; reconstitution; screening; tool; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Protein quality control operates in cells to limit levels misfolded proteins. It is critical for normal cell health and underlies many diseases. A key branch of quality control (QC) involves ubiquitin-mediated proteolysis of misfolded proteins. We have recently discovered that the highly conserved E3 ubiquitin ligase Ubr1 has a previously unknown role in cytoplasmic quality control, by which aberrant proteins are degraded by Ubr1- mediated ubiquitination. Ubr1 is well-known for its role in the "N-end rule", but the newly discovered QC functions of Ubr1 operate independently of these previously described actions. In cytoplasmic quality control, Ubr1 uses a chaperone-dependent mechanism to specifically ubiquitinate a wide variety of misfolded proteins. Furthermore, the Ubr1 QC pathway is physiologically relevant, since it is needed to survive proteotoxic cellular stress. In the proposed studies, we will completely characterize the action and role of Ubr1 in protein quality control, using genetic, molecular biological, and biochemical approaches. The studies span a range of questions, including the variety and characteristics of misfolded protein substrates, the features of Ubr1 required for its quality control function, the role of chaperones on the pathway, and the physiological functions Ubr1-mediated quality control the living cell. Our work on Ubr1-mediated quality control is medically relevant due to the importance of quality control in the etiology of some our society's pressing maladies, and because UBR ligases are highly conserved in all eukaryotes. Loss of UBR ligase functions in mammals causes many detrimental phenotypes, including the mutations of human UBR1 responsible for the severe Johanson-Blizzard syndrome. We believe that the quality control actions of UBR ubiquitin ligases will underlie many aspects of their function in all organisms. Our studies will define those functions and eventually the ways to harness or quell them for basic and biomedical benefit.

描述（由申请方提供）：在细胞中进行蛋白质质量控制，以限制错误折叠蛋白质的水平。它对正常细胞健康至关重要，是许多疾病的基础。质量控制（QC）的一个关键分支涉及错误折叠蛋白的泛素介导的蛋白水解。我们最近发现，高度保守的E3泛素连接酶Ubr 1在细胞质质量控制中具有以前未知的作用，通过Ubr 1介导的泛素化降解异常蛋白。Ubr 1以其在“N端规则”中的作用而闻名，但新发现的Ubr 1的QC功能独立于这些先前描述的操作。在细胞质质量控制中，Ubr 1使用分子伴侣依赖性机制来特异性地泛素化多种错误折叠的蛋白质。此外，Ubr 1 QC途径是生理学相关的，因为它需要在蛋白毒性细胞应激中存活。 在拟议的研究中，我们将使用遗传学，分子生物学和生物化学方法，完全表征Ubr 1在蛋白质质量控制中的作用和作用。这些研究涵盖了一系列问题，包括错误折叠蛋白质底物的种类和特征，Ubr 1质量控制功能所需的特征，分子伴侣在该途径中的作用，以及Ubr 1介导的活细胞质量控制的生理功能。 我们对UBR 1介导的质量控制的工作是医学相关的，由于质量控制在我们社会的一些紧迫疾病的病因学的重要性，因为UBR连接酶在所有真核生物中是高度保守的。哺乳动物中UBR连接酶功能的丧失导致许多有害的表型，包括导致严重Johanson-Blizzard综合征的人类UBR 1突变。我们相信UBR泛素连接酶的质量控制作用将成为它们在所有生物体中功能的许多方面的基础。我们的研究将定义这些功能，并最终确定利用或抑制它们的方法，以获得基本的生物医学利益。