CRYSTAL STRUCTURES OF THE UBIQUITIN LIGASES

泛素连接酶的晶体结构

• 批准号: 8363353
• 负责人: Bing Hao
• 金额: $ 0.38万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363353
• 关键词: Biological Models; Cell Cycle; Cell Cycle Regulation; Cell physiology; Crystallography; Cyclin-Dependent Kinases; Cyclins; Defect; Eukaryotic Cell; Funding; Genomic Instability; Goals; Grant; Knowledge; Lead; Light; Lysine; Malignant Neoplasms; National Center for Research Resources; Neurodegenerative Disorders; Play; Principal Investigator; Proteolysis; Regulation; Research; Research Infrastructure; Resources; Role; SKP Cullin F-Box Protein Ligases; Series; Source; Specificity; Structure; Synchrotrons; System; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; United States National Institutes of Health; base; cost; inhibitor/antagonist; tool; ubiquitin ligase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This research is focused on understanding how the cell cycle is regulated by ubiquitin-mediated proteolysis using x-ray crystallography as a primary tool. Progression through the cell cycle is coordinated by the cyclin-dependent kinases (CDKs) and their activating cyclin subunits as well as a series of CKI inhibitors. Control of the oscillations of the cyclins and CKIs by ubiquitin-dependent proteolysis plays a critical role in cell cycle regulation. Deregulation of the cyclins and CKIs can cause aberrant proliferation and genomic instability. Indeed, the eukaryotic cell cycle is one of the most frequently altered cellular processes identified in cancer. The overall goal of this research is to use SCF ubiquitin ligases as a model system to elucidate the structural and mechanistic basis of substrate recognition, lysine specificity, ubiquitin transfer, and the role of CDK in CKI degradation. My long-term objective is to gain a detailed understanding of the structure, function, and regulation of APC/C and Cul3-based ubiquitin ligases, and to use this knowledge to elucidate how defects of the ubiquitin system can lead to cancer and neurodegenerative diseases.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这项研究的重点是了解细胞周期是如何通过泛素介导的蛋白水解，使用X射线晶体学作为主要工具。 细胞周期的进程由细胞周期蛋白依赖性激酶（CDK）及其活化细胞周期蛋白亚基以及一系列CKI抑制剂协调。 通过遍在蛋白依赖性蛋白水解控制细胞周期蛋白和CKI的振荡在细胞周期调节中发挥着关键作用。 细胞周期蛋白和CKIs的失调可导致异常增殖和基因组不稳定。 事实上，真核细胞周期是癌症中发现的最常改变的细胞过程之一。 本研究的总体目标是使用SCF泛素连接酶作为模型系统，以阐明底物识别，赖氨酸特异性，泛素转移的结构和机制基础，以及CDK在CKI降解中的作用。 我的长期目标是详细了解APC/C和Cul 3泛素连接酶的结构、功能和调控，并利用这些知识阐明泛素系统的缺陷如何导致癌症和神经退行性疾病。