The ubiquitin-dependent activation of kinases

细胞通过接收信号的各种探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的反应。信号转导途径包括许多组件，这些组件都编织在一起，看起来像是由相互连接的组件组成的不可能的网络，就像电话交换机内部一样。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枢。这些中枢在特定的时刻被一种名为泛素的蛋白质启动。泛素可以组装成长聚合物，就像绳子上的珠子一样，泛素可以通过不同的方式自组装，产生定义的代码。我将确定某些信号中枢是如何受泛素调节的，并知道如何传递适当的反应。我感兴趣的信号中枢驻留在关键的细胞通路中，这些通路对于细胞对病原体感染或外部信号的反应至关重要。对这些信号的解释对细胞的生存至关重要：从炎症性疾病、某些癌症到神经系统疾病，人类的几种疾病都是由这些信号中枢的缺陷引起的。我理解这些信号枢纽的规则的方法包括重组和分析单独的组件，然后一起建造综合体。采用这种方法可以确保仔细分析每个组成部分的功能，并了解其功能。我将使用生化和生物物理技术的工具包来了解泛素密码是如何能够调节特定的信号中枢子集的，我将获得分子快照，提供与泛素结合的激活信号中枢的三维结构。了解这些被激活的中枢的结构将首次让我们得以一窥整个建筑群是如何受到监管的。此外，该结构将为这些枢纽中的特定基因突变如何导致某些疾病提供解释。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南，这些化合物扰乱这些信号中枢依赖泛素的激活，因此可能为这些疾病提供新的替代治疗方法。因此，我的研究将对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取得进展。

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.