Chemical tools for studying conventional and non-conventional modes of ubiquitylation

用于研究常规和非常规泛素化模式的化学工具

• 批准号: MC_UU_00018/7
• 负责人: Satpal Virdee
• 金额: $ 325.81万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00018%2F7
• 关键词: Chemical; tools; studying; conventional; non

Our health and well-being are dependent on the correct functioning of the cells in our body. It is therefore imperative that we have a thorough understanding of the biochemical processes that take place within them. It is these processes that become faulty in certain diseases therefore being armed with the knowledge of their intricacies will place in a position where we can rationally develop new therapies that alleviate their symptoms of or even cure them.A cellular regulatory mechanism that affects all processes is known as protein ubiquitylation. Protein ubiquitylation involves the attachment of a small protein called ubiquitin to other proteins. This step is carried out by enzymes known as E3. Challenges with fully understanding protein ubiquitylation arise from a lack of research technologies that enable the activities of even a single E3 in a cell to be measured. Additionally, we now have strong knowledge about which proteins are tagged with ubiquitin but our ability to identify the E3 responsible is extremely difficult and new tools are urgently needed.We have recently developed some exciting and powerful technology that allows not only a single E3s activity in a cell to be measured, but the activity of tens of E3s to be measured simultaneously. This technology will revolutionise our ability to understand the roles of E3s and protein ubiquitylation in both normal and diseased cells.

我们的健康和幸福取决于我们体内细胞的正常运作。因此，我们必须彻底了解其中发生的生化过程。正是这些过程在某些疾病中变得有缺陷，因此掌握了它们的复杂性的知识将使我们能够合理地开发新的疗法来减轻症状甚至治愈它们。影响所有过程的细胞调节机制被称为蛋白质泛素化。蛋白质泛素化涉及一种叫做泛素的小蛋白质与其他蛋白质的连接。这一步是由称为E3的酶进行的。充分理解蛋白质泛素化的挑战来自于缺乏研究技术，即使是细胞中单个E3的活性也无法测量。此外，我们现在对哪些蛋白质被泛素标记有很强的了解，但我们鉴定E3的能力是非常困难的，迫切需要新的工具。我们最近开发了一些令人兴奋和强大的技术，不仅可以测量细胞中单个E3的活性，而且可以同时测量数十个E3的活性。这项技术将彻底改变我们理解E3和蛋白质泛素化在正常和病变细胞中的作用的能力。

项目成果

An Atypical E3 Ligase Module in UBR4 Mediates Destabilization of N-degron Substrates

• DOI: 10.1101/2023.05.08.539884
• 发表时间: 2023-05
• 期刊: bioRxiv
• 作者: Lucy Barnsby-Greer;P. D. Mabbitt;M. Déry;Daniel R. Squair;N. Wood;S. Lange;S. Virdee

Selective Inhibition of Cysteine-Dependent Enzymes by Bioorthogonal Tethering.

• DOI: 10.1016/j.jmb.2022.167524
• 发表时间: 2022-03
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Luke A. Spear;Yang Huang;Jinghao Chen-;Alexander R Nödling;S. Virdee;Y. Tsai

Activity-based probe profiling of RNF12 E3 ubiquitin ligase function in Tonne-Kalscheuer syndrome.

• DOI: 10.26508/lsa.202101248
• 发表时间: 2022-11
• 期刊: LIFE SCIENCE ALLIANCE
• 影响因子: 4.4
• 作者: Bustos, Francisco;Mathur, Sunil;Espejo-Serrano, Carmen;Toth, Rachel;Hastie, C. James;Virdee, Satpal;Findlay, Greg M.
• 通讯作者: Findlay, Greg M.

Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.

• DOI: 10.1038/s41589-020-0598-6
• 发表时间: 2020-11
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Mabbitt PD;Loreto A;Déry MA;Fletcher AJ;Stanley M;Pao KC;Wood NT;Coleman MP;Virdee S
• 通讯作者: Virdee S

Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability.

• DOI: 10.1016/j.molcel.2018.02.023
• 发表时间: 2018-04-05
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Kwasna D;Abdul Rehman SA;Natarajan J;Matthews S;Madden R;De Cesare V;Weidlich S;Virdee S;Ahel I;Gibbs-Seymour I;Kulathu Y
• 通讯作者: Kulathu Y