Bidentate Molecular Probes for Hect. E3 Ubiquitin Ligase Biological Function

Hect 的双齿分子探针。

• 批准号: 1644180
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1644180
• 关键词: Bidentate; Molecular; Probes; Hect.; E3

Protein ubiquitination represents a post-translational modification that regulates a variety of cellular processes including protein turnover, trafficking, sub-cellular localisation, transcriptional function and DNA repair mechanisms. Ubiquitin conjugation involves a cascade of events catalysed sequentially by E1 (ubiquitin-activating), E2 (ubiquitin conjugating), and E3 (ubiquitin ligase) enzymes. This project will focus on the development of novel bivalent molecular probes to elucidate the biological roles and substrate-specific function of a small well-defined sub-group known as the HECT E3 ubiquitin ligases. Of particular interest will be the NEDD4-like E3 ubiquitin-protein ligases WWP1 and WWP2. The latter binds to SMAD proteins in the TGF- signalling pathway, targeting them for degradation. The combined strengths of the lead applicants in advanced Cell/Molecular Biology and Synthetic Chemistry, together with cross-fertilization of new ideas and disciplines, will facilitate novel approaches to elucidate the dynamics of fundamental protein ubiquitination mechanisms. The use of simple chemical tools to probe the function and importance of individual components of complex biochemical pathways/networks clearly fits within the BBSRC remit. The student will embrace a range of techniques (chemical synthesis, mechanistic enzymology, whole cell studies) to probe the functionality of different ligands at both the cellular and molecular level. This is a subject area relevant to BBSRC research priorities at the Chemistry-Biology interface. The outputs of this project could also lead to the next generation of selective inhibitors of cell growth, which would be of great interest for further study and development to produce improved cancer chemotherapeutics. Supporting research that is likely to have a beneficial impact in terms of knowledge transfer, commercialisation and healthcare benefits) is an increasingly important priority within BBSRC.

蛋白质泛素化是一种翻译后修饰，可调节多种细胞过程，包括蛋白质周转、运输、亚细胞定位、转录功能和DNA修复机制。泛素缀合涉及由E1（泛素活化）、E2（泛素缀合）和E3（泛素连接酶）依次催化的级联事件。该项目将专注于开发新型二价分子探针，以阐明一个小的定义明确的亚组称为HECT E3泛素连接酶的生物学作用和底物特异性功能。特别感兴趣的是NEDD 4样E3泛素蛋白连接酶WWP 1和WWP 2。后者在TGF-信号通路中与SMAD蛋白结合，靶向它们进行降解。领先申请人在先进的细胞/分子生物学和合成化学方面的综合优势，以及新思想和学科的交叉融合，将促进新方法来阐明基本蛋白质泛素化机制的动态。使用简单的化学工具来探测复杂的生化途径/网络的单个组分的功能和重要性显然符合BBSRC的职权范围。学生将接受一系列技术（化学合成，机械酶学，全细胞研究），以探测不同配体在细胞和分子水平上的功能。这是一个与化学-生物学接口的BBSRC研究优先事项相关的主题领域。该项目的成果还可能导致下一代细胞生长的选择性抑制剂，这将对进一步研究和开发以生产改进的癌症化疗药物产生极大的兴趣。支持可能在知识转移、商业化和医疗保健方面产生有益影响的研究是BBSRC越来越重要的优先事项。