Development of novel crosslinking-mass spectrometry technologies to interrogate the molecular sociology of cells

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Context of researchBiological processes are undertaken by an intricate network of transiently interacting protein assemblies. Uncovering this 'molecular sociology' of the cell is vital to understanding cellular homeostasis and disease mechanisms, but to achieve this, new tools are urgently needed. Aims and objectives - The objectives are:Chemical crosslinking combined with mass spectrometry can be used to identify protein-protein interactions in cells, to reveal this 'molecular sociology'. However, new crosslinkers are needed to overcome experimental challenges. In this project you will design/synthesise novel chemical crosslinkers and validate these reagents for protein structure/interaction analysis in cells. Potential applications and benefitsThis interdisciplinary project will encompass synthetic and analytical chemistry, biological chemistry and cell biology. You will design and synthesize a panel of crosslinkers with functionalities that address the methodological challenges encountered in crosslinking workflows for cellular structural biology. Next, you will validate analytical workflows for these crosslinker designs for in vitro and in cell protein interaction analysis by mass spectrometry-based proteomics. Finally, you will exemplify the functionality of these novel crosslinkers as chemical tools by studying cellular models of cardiovascular disease and protein misfolding/aggregation diseases (e.g. Parkinson's and Alzheimer's diseases). The outcome will be a range of crosslinking reagents with optimised properties that will transform our ability to interrogate biological mechanisms directly in cells.Research Areas: Biological mechanisms in cells.Qualification to be attained: PhD degree