Ubiquitin and Ub-like interactomes in regulation of cellular functions

泛素和 Ub 样相互作用组在细胞功能调节中的作用

• 批准号: 27748112
• 负责人: Professor Dr. Ivan Dikic
• 金额: --
• 依托单位: Institut für Biochemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/27748112?language=en
• 关键词: Ubiquitin; Ub; like; interactomes; regulation

Protein ubiquitylation (ubiquitination), the attachment of a small polypeptide ubiquitin (Ub) to protein substrates, is an evolutionary conserved mechanism that controls a wide variety of cellular functions, including proteasomal degradation, intracellular trafficking, DNA repair, gene transcription and virus budding. Our recent discovery of novel Ub-binding domains has indicated how Ub may specifically regulate distinct functions of ubiquitylated targets. There are several Ub-like modifiers, e.g. SUMO, FAT10, ISG15, etc., which trigger various cellular responses. Here we propose to clone small binding domains involved in specific recognition of Ub and Ub-like modifiers by using a large-scale yeast-two-hybrid system coupled with bioinformatics, biochemistry, molecular biology and nuclear magnetic resonance (NMR) spectroscopy work. This will lead to detailed mapping of Ub- and Ubl-specific networks tracing the formation of protein-protein interactomes in cells. The information thus gained will be tested in different cell biological systems to evaluate their physiological and pathophysiological functions. Understanding the specificity of Ub and Ub-like interactomes in vivo will have wide implications for biology and medicine as well as for modern therapeutic approaches to human diseases.

蛋白质泛素化（ubiquitination），即小多肽泛素 (Ub) 与蛋白质底物的附着，是一种进化保守机制，控制多种细胞功能，包括蛋白酶体降解、细胞内运输、DNA 修复、基因转录和病毒出芽。我们最近发现的新型 Ub 结合域表明 Ub 如何特异性调节泛素化靶标的不同功能。有几个类似 Ub 的修饰符，例如SUMO、FAT10、ISG15等，触发各种细胞反应。在这里，我们建议通过使用大规模酵母双杂交系统，结合生物信息学、生物化学、分子生物学和核磁共振（NMR）波谱工作，克隆参与特异性识别 Ub 和 Ub 样修饰剂的小结合域。这将导致 Ub 和 Ubl 特异性网络的详细绘制，追踪细胞中蛋白质-蛋白质相互作用组的形成。由此获得的信息将在不同的细胞生物系统中进行测试，以评估其生理和病理生理功能。了解体内 Ub 和类 Ub 相互作用组的特异性将对生物学和医学以及人类疾病的现代治疗方法产生广泛的影响。