Inside every human cell, a protein called ubiquitin assembles into long chains that act like molecular switches, flipping on critical signalling hubs that tell the cell how to respond to infection or injury. When these switches malfunction, the consequences include inflammatory diseases, certain cancers, and neurological disorders such as Crohn’s disease and amyotrophic lateral sclerosis. The problem is that no one knows exactly how ubiquitin chains activate these hubs. This project will reconstitute the signalling complexes piece by piece, using biochemical and biophysical techniques to capture three-dimensional snapshots of the activated hub bound to ubiquitin. For the first time, this will reveal the structural mechanism that governs the switch. If successful, the work will explain how specific genetic mutations in these hubs cause disease. The structures will also serve as blueprints for designing new compounds that disrupt faulty ubiquitin-dependent activation, potentially leading to alternative treatments. This is fundamental science with no immediate clinical application, but understanding how these molecular decision-making hubs work is a necessary step before anyone can fix them when they break.
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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.
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