About the Project
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 email@example.com
HOW TO APPLY
Applications should be made by emailing firstname.lastname@example.org with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.
In addition to the CV and covering letter, please email a completed copy of the NLD BBSRC DTP Studentship Application Details Form (Word document) to email@example.com, noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
2. Maturation of the functional mouse CRES amyloid from globular form. Proc Natl Acad Sci U S A. 2020 117:16363-16372.
3. In silico prediction of structure and function for a large family of transmembrane proteins that includes human Tmem41b BioRXiv doi: https://doi.org/10.1101/2020.06.27.174763.
4. From Protein Structure to Function with Bioinformatics. 2nd edition. Springer, Dordrecht, 2017. (edited)
5. The Generation of a Comprehensive Spectral Library for the Analysis of the Guinea Pig Proteome by SWATH-MS. Proteomics.2019 19: e1900156.
6. Inhibition of Inflammatory Changes in Human Myometrial Cells by Cell Penetrating Peptide and Small Molecule Inhibitors of NFκB. Front Immunol. 2018 9:2966.
7. Insights into peptide inhibition of alpha-synuclein aggregation, Front Neurosci, doi: 10.3389/fnins.2020.561462
8. Cyclophilin D binds to the acidic C-terminus region of alpha-Synuclein and affects its aggregation characteristics. Sci Rep. 2020, 10, 10159
9. Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction. Biophys J. 2020, 118, 2769-2782
10. Isolation and purification of recombinant immunoglobulin light chain variable domains from the periplasmic space of Escherichia coli, PLOS One, 2018, 13, e0206167
Based on your current searches we recommend the following search filters.
Based on your current search criteria we thought you might be interested in these.