Amyloid proteins are biologically fascinating, with many aspects of their formation and interaction poorly understood, and are intimately involved in a variety of human diseases. Typically regarded as the result of pathological misfolding, for some proteins (mainly bacterial proteins) amyloid is the normal functional structure. Recent work shows that these proteins, found on the surface of gut bacteria, can interact with host proteins that are also capable of (mis)folding into an amyloid state with potential relevance for conditions such as Parkinson’s and Alzheimer’s diseases. At present, only a few bacterial functional amyloid proteins have been characterised and much remains poorly understood about their interaction with host proteins. This project aims to discover new families of bacterial function amyloid proteins and probe their interaction with host proteins, cells and systems.
Bacterial functional amyloid proteins adopt a B-helical structure and are built of repeating sequences with each repeat contributing a number of layers of the B-helix. The bioinformatics discovery phase of the project therefore centres on revealing unsuspected repeat proteins, then deploying state of the art ab initio structure prediction methods, as exemplified by Google AlphaFold, to test whether they adopt a B-helical structure. These methods have made huge advances in recent years and have broad applicability across the protein universe: the successful applicant will therefore gain hugely valuable experience in this fast-moving area.
Following identification of potential candidate proteins will be recombinantly expressed and ability to form amyloid and interactions with host proteins assessed using a range of experimental techniques. Effect of microbial proteins on cell biological function will be probed at the second institution by studying the effect on cell signalling pathways in smooth muscle and endothelial cells.
This project will provide training in biochemical and biophysical techniques and cell signalling to complement novel bioinformatics skills. The aims of this project are to enhance understanding of the interactions between bacterial and host proteins, along with increased knowledge of the process and impact of novel structural re-arrangements that can occur upon protein-protein interaction. This knowledge has the potential to understand the role of potentially pathogenic bacteria introduced via the gut microbiome or infection in a range of health and disease situations.
Informal enquiries may be made to Dr Jill Madine: [Email Address Removed]
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