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The role of TonB in the function of outer membrane virulence factors


Project Description

The outer membrane of Gram negative bacteria is a highly effective protective barrier but it is problematic for the transport of molecules due to its impermeability and the lack of an energy source. TonB dependent transporters (TBDTs) of Gram negative bacteria bind to and transport scarce but vital nutrients across the otherwise impermeable outer membrane by binding to TonB – an inner membrane protein that traverses the periplasm.

As TBDTs are virulence factors, they have potential as a novel anti-bacterial drug targets but the mechanism by which TonB catalyses transport across the membrane is still unclear. We have recently identified a novel and unexpected conformational switch in the periplasm-spanning linker domain of TonB that may drive the active transport of TBDT cargo (Gating of TonB dependent transporters by substrate-specific forced remodeling (Hickman et al. (2017) Nature Commun. 8: article no. 14804))

The aim of the project is to use force spectroscopy methods developed in the Brockwell lab together with molecular dynamics simulations of the process (Dr Paci) to visualize the structural that TonB undergoes. The consequences of preventing this conformational switch will then be assessed in vivo using a wealth of growth and phenotype assays, leading the way for drug development.

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.

There are 2 stages to the application process. Please see our website for more information: View Website

References

1. Inducing protein aggregation by extensional flow. Dobson, J., Kumar, A., Willis, L., Tuma, R., R. Higazi, D., Turner, R., Lowe, D., Ashcroft, A., Radford, S., Kapur, N. and Brockwell, D. (2017) Proc Natl Acad Sci USA. 114:4673-4678.
2. Gating of TonB dependent transporters by substrate-specific forced remodeling. Hickman, S., Cooper, R., Belluci, L., Paci, E. and Brockwell, D. (2017) Nature Commun. 8: article no. 14804
3. Cooperative folding of intrinsically disordered domains drives assembly of a strong elongated protein. Gruszka,. D., Whelan, F., Farrance, O., Fung, H., Paci, E., Jeffries, C., Svergun, D., Baldock, C., Baumann, C., Brockwell, D., Potts, J. and Clarke, J. (2015) Nat Commun 6: article no. 7271.
4. Disorder drives cooperative folding in a multidomain protein
DT Gruszka, CATF Mendonça, E Paci, F Whelan, J Hawkhead, JR Potts, Clarke, J Proc Natl Acad Sci USA 113 (42), 11841-11846

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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