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Bacterial chemical harpoons – how do TIE proteins function?

  • Full or part time
    Dr U Schwarz-Linek
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

In order to colonise a host and cause infections, bacteria need to gain a foothold by adhering to tissues such as cell surfaces. In general this is achieved through specific interactions between proteins and multimeric protein assemblies (pili) presented on the bacterial surface, and host molecules. A new class of bacterial adhesion factors called TIE proteins contain reactive thioester bonds and bind to their host receptors through formation of a covalent bond. This is assumed to results in fast, very tight binding, and may be the first step in many adhesion processes of Gram-positive bacteria. The mode of action, binding partners and biological role of TIE proteins are largely unknown.
In this project you will characterise TIE proteins of highly relevant human pathogens such as Enterococcus faecium and Streptococcus pyogenes, and study their interactions with mammalian tissues. You will identify binding targets of TIE proteins, and aim to elucidate the structures of TIE protein complexes. This will be an important step towards understanding the biological role of this exciting class of bacterial proteins and will provide the required information for the design of inhibitors of bacterial adhesion. You will also develop novel approaches to visualise TIE proteins on bacterial surfaces, for instance to facilitate imaging of TIE proteins by cryo-EM.
You will be trained in a wide range of methods, mainly structural biology (NMR and crystallography, cryo-EM through collaboration), biophysical techniques for molecular interactions (e.g. microcalorimetry, SPR), and cell-based adhesion assays. We apply and develop novel protein-based tools for molecular interaction analyses. Through collaborations you will also engage with synthetic chemists and microbiologists.
An interest in proteins, microbiology and structural biology is essential; prior experience of protein biochemistry, molecular biology, or structural biology would be beneficial. We are part of the Biomedical Sciences Research Complex, an interdisciplinary institute with a vibrant postgraduate community and excellent research facilities. Our group collaborates with microbiologists, microscopists and chemists in the UK and elsewhere in the world.
Informal enquiries are encouraged. Please contact the project supervisor Dr Uli Schwarz-Linek ().

Funding Notes

Eligibility requirements: Upper second-class degree in the life sciences or chemistry
Funding: Fees and stipend is provided for 3.5 years.

References

Miller, O.K., Banfield, M.J., Schwarz-Linek, U. A new structural class of bacterial thioester domains reveals a slipknot topology. Protein Sci. 57:5996-6002 (2018) https://doi.org/10.1002/pro.3478
Walden, M., Edwards, J.M., Dziewulska, A.M., Bergmann, R., Saalbach, G. Kan, S.-Y., Miller, O.K., Weckener, M., Jackson, R.J., Shirran, S.L. Botting, C.H., Florence, G.J., Rohde, M., Banfield, M.J., Schwarz-Linek, U. An internal thioester in a pathogen surface protein mediates covalent host binding. eLife 4:e06638 (2015) https://doi.org/10.7554/eLife.06638.001

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

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