The ubiquitin-dependent activation of kinases

泛素依赖性激酶激活

• 批准号: MR/R008582/1
• 负责人: Paul Elliott
• 金额: $ 168.37万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR008582%2F1
• 关键词: ubiquitin; dependent; activation; kinases

Cells respond and adapt to various internal and external stimuli through a variety of detectors, which receive the signal. The signal orchestrates the cell response through a signal transduction pathway. Signal transduction pathways involve numerous components all woven together in what seems like an impossible meshwork of interconnecting components, much like inside a telephone exchange. Therefore, to ensure that a correct signal is propagated and transmitted, key decision making hubs that interpret the incoming signal and define the output are required. These hubs are switched on at defined moments by a protein called ubiquitin. Ubiquitin can be assembled into long polymers, just like beads on a string, and the different ways in which ubiquitin can be self-assembled, results in defined codes.I will determine how certain signalling hubs are regulated by ubiquitin and know how to transmit an appropriate response. The signalling hubs that I am interested in reside in crucial cellular pathways that are vital for cells to respond to infection by a pathogen or to external signals. Interpretation of these signals is vital for cellular survival: several human diseases ranging from inflammatory diseases, certain cancers and neurological disorders all arise from defects within these signalling hubs. My approach to understanding the regulation of these signalling hubs involves reconstitution and analysis of the separate components followed by building the complex together. Taking such an approach ensures that the function of each component can be carefully analysed and the function of it can be understood. I will use a toolkit of biochemical and biophysical techniques to understand how the ubiquitin code is able to regulate a defined subset of signalling hubs and I will obtain molecular snap-shots that will provide the three-dimensional structure of the activated signalling hub bound to ubiquitin. Understanding the structure of these activated hubs will, for the first time, provide a glimpse into how the entire complex is regulated. Furthermore, the structure will provide an explanation of how particular genetic mutations in these hubs leads to certain diseases. For example, Crohn's disease and amyotrophic lateral sclerosis. In addition, the structures will serve as a guide for the development of new compounds that disrupt the ubiquitin-dependent activation of these signalling hubs and therefore may offer new alternative treatments for these diseases. Therefore, my research will progress the knowledge of how and why these signalling events can go astray in a number of human diseases.

细胞通过接收信号的各种检测器对各种内部和外部刺激做出反应和适应。该信号通过信号转导途径协调细胞反应。信号转导通路涉及众多组件，这些组件编织在一起，看起来像是一个不可能的互连组件网络，就像电话交换机一样。因此，为了确保传播和传输正确的信号，需要解释传入信号并定义输出的关键决策中心。这些枢纽在特定的时刻被一种叫做泛素的蛋白质打开。泛素可以组装成长的聚合物，就像一根绳子上的珠子，泛素可以自组装的不同方式，导致定义的代码。我将确定某些信号中枢是如何被泛素调节的，并知道如何传递适当的反应。我感兴趣的信号中枢位于关键的细胞通路中，这些通路对于细胞对病原体感染或外部信号做出反应至关重要。这些信号的解释对于细胞存活至关重要：从炎症性疾病，某些癌症和神经系统疾病等几种人类疾病都是由这些信号中枢内的缺陷引起的。我理解这些信号枢纽的调节的方法包括重组和分析单独的组件，然后一起构建复合体。采用这种方法可确保仔细分析每个组成部分的功能，并了解其功能。我将使用生物化学和生物物理技术的工具包，以了解泛素代码是如何能够调节一个定义的子集的信号枢纽，我将获得分子快照，将提供三维结构的激活信号枢纽绑定到泛素。了解这些激活的枢纽的结构将首次提供对整个复合体如何调节的一瞥。此外，该结构将解释这些枢纽中的特定基因突变如何导致某些疾病。例如，克罗恩病和肌萎缩侧索硬化症。此外，这些结构将作为开发新化合物的指导，这些化合物破坏了这些信号中枢的泛素依赖性激活，因此可能为这些疾病提供新的替代治疗方法。因此，我的研究将进一步了解这些信号事件如何以及为什么会在许多人类疾病中误入歧途。

项目成果

Structural basis for antagonism of the ubiquitin ligase BIRC6 by SMAC

• DOI: 10.1101/2022.08.30.505748
• 发表时间: 2022-08
• 期刊: bioRxiv
• 作者: Larissa Dietz;Cara J. Ellison;Carlos Riechmann;C. K. Cassidy;F. D. Felfoldi;Adán Pinto-Fernández;B. Kessler;P. R. Elliott

Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.

• DOI: 10.1016/j.celrep.2021.109777
• 发表时间: 2021-10-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Elliott PR;Leske D;Wagstaff J;Schlicher L;Berridge G;Maslen S;Timmermann F;Ma B;Fischer R;Freund SMV;Komander D;Gyrd-Hansen M
• 通讯作者: Gyrd-Hansen M

Sex-specific deubiquitylation drives immune-related neurodegeneration in Drosophila

• DOI: 10.1101/2022.12.09.519782
• 发表时间: 2022-12
• 期刊: bioRxiv
• 作者: Jingnu Xia;Adán Pinto-Fernández;Andreas C. Damianou;Jeffery Y Lee;B. Kessler;Ilan Davis;Paul Elliott-Paul-Elli