The Cullin-ROC Family of E3 Ubiquitin Ligases

E3 泛素连接酶的 Cullin-ROC 家族

• 批准号: 7336780
• 负责人: YUE XIONG
• 金额: $ 30.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336780
• 关键词: Back; Binding; Biochemical; CDT1 Gene; CUL3 gene; CUL4A gene; Cell Proliferation; Cell physiology; Computer Simulation; DNA Damage; DNA Replication Factor; Family; Genetic; Genetic Transcription; Goals; Investigation; Knockout Mice; Licensing Factor; Ligase; Mitosis; Mitotic; Mutant Strains Mice; Numbers; Play; Protein Binding; Proteins; Proteomics; RBX1 gene; Recruitment Activity; Regulation; Replication Licensing; Research; Research Personnel; Role; Series; Transcriptional Regulation; Zinc Fingers; base; in vivo; numb protein; response; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): This is the first competitive renewal of GM067113, an investigation aimed at the long term goal of understanding the function and regulation of cullin-RING family of E3 ubiquitin ligases (CRLs). Looking back at the journey of the past several years, we are very pleased to see the contribution we made and more remarkably, the advancements achieved collectively by colleagues. Following the initial discovery of ROC1 and ROC2, we have made several findings toward this goal. These include: (1) that CAND1, an evolutionary conserved cullin-associated and neddylation dissociated protein, controls substrate recruitment to all CRLs, (2) that CUL3 binds to a BTB motif present in more than 200 mammalian proteins and potentially assembles a large number of BTB-CUL3-ROC1 ligases, (3) that DDB1-CUL4-ROC1 ligase target the replication licensing factor CDT1 for degradation in response to DNA damage, and (4) that CUL4 interacts with large number of cellular proteins, and (5) that pl70(KIAA080), an evolutionarily-conserved WD40 protein, binds abundantly with CUL4A via DDB1 and plays an essential role in cellular proliferation in a p53-dependent manner. With these series of findings as the basis, we propose a further research to elucidate the substrate- recruitment mechanism, the cellular function and regulation of CUL3- and CUL4-dependent ubiquitin ligases. The studies outlined in this proposal combine computer modeling, proteomic, biochemical, cellular and genetic approaches, offering an excellent and unique opportunity to help in the understanding of the largest family of E3 ubiquitin ligases. Three specific aims are: (i) to determine the functions and substrates of CRLS in mitosis and in transcriptional regulation, (ii) to determine the substrate recruiting mechanism of CRL4 ligases, and (iii) to determine the function and mechanism of p170.

描述（由申请人提供）：这是GM067113的第一个竞争续订，该调查旨在长期目标，以了解E3泛素连接酶（CRLS）的Cullin-Ring家族的功能和调节。回顾过去几年的旅程，我们很高兴看到我们所做的贡献，更引人注目的是同事们共同取得的进步。在最初发现ROC1和ROC2之后，我们针对这个目标做出了一些发现。其中包括：（1）CAND1是一种进化保守的cullin相关和nEddyDymation解离蛋白，控制底物募集到所有CRLS中，（2）CUL3与存在于200多个哺乳动物蛋白中的BTB基序结合了200多个哺乳动物的细蛋白，并在200个以上的哺乳动物priocation和潜在的btb-cul3-rig1 lig1 lig1 lig1 lig1-cul asse（3）rig1-cul asse（3）。复制许可因子CDT1用于响应DNA损伤的降解，（4）CUL4与大量细胞蛋白相互作用，（5）PL70（KIAA080）（一种进化保存的WD40蛋白）（kiaa080）与Cul4a通过ddb1和Cell o and Ordent Ornection and o and of Ansiver con nory con pp53 top53 pp53 dyd3 dyd3 dyd3 dyd33蛋白质相结合。以这些系列发现为基础，我们提出了一项进一步的研究，以阐明底物募集机制，CUL3-和CUL4依赖性泛素连接酶的细胞功能和调节。该提案中概述的研究结合了计算机建模，蛋白质组学，生化，细胞和遗传方法，提供了一个极好的独特机会，以帮助理解最大的E3泛素连接酶家族。三个具体目的是：（i）确定CRL在有丝分裂和转录调控中的功能和底物，（ii）确定CRL4连接酶的底物募集机制，以及（III）以确定P170的功能和机制。