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Dissecting the role of a membrane-associated bacterioferritin complex in Neisseria gonorrhoeae


School of Natural and Environmental Sciences

Dr J Marles-Wright , Dr K Djoko , Dr K Waldron Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biochemistry Microbiology Structural Biology

About the Project

Bacterial infection is a fact of life. Antibiotics have considerably reduced mortality, but the spread of antibiotic resistance threatens to impede infectious disease control and compromise basic aspects of healthcare that we take for granted. In the UK ~44,000 deaths occur every year from untreatable bacterial infections, costing the NHS £2 billion annually.

Iron is a vital cofactor for many enzymes, and bacteria must ensure that they have an adequate supply of this essential nutrient. Upon infection by microorganisms, the animal host innate immune system typically reduces the availability of iron. In response, bacteria activate pathways for metal import, metal sparing, or metal storage to avoid stress from metal starvation. This competition for metals is termed “nutritional immunity”. Ferritin proteins are the primary iron stores in all kingdoms of life, they act to oxidise and sequester iron in a bioavailable mineral form within a hollow protein cage. Some bacteria possess heme-binding bacterioferritins, which allow the rapid mobilisation of stored iron through electron transfer via the heme group.

You will study a membrane associated bacterioferritin complex from the Gram-negative pathogen Neisseria gonorrhoeae. This pathogen has been identified as a “superbug”, with multiple strains and isolates that have become completely resistant to all last-line antibiotics. It is not surprising that this pathogen is listed by the Centre of Disease Control (USA), the World Health Organisation, and Public Health UK as a research priority.

Goals and Objectives:

1) You will produce recombinant bacterioferritin complexes, for structural and functional analyses to understand how iron is stored within the compartment.

2) You will use modern structural biology techniques, including X-ray crystallography and electron microscopy, to analyse the molecular structure of the bacterioferritin complex.

3) You will make targeted gene knockouts in Neisseria gonorrhoea of the individual bacterioferritin components to understand their role in the physiology and pathogenicity of this bacterium.

Supervision:

You will be based in the laboratory of the primary supervisor at Newcastle University, and work closely with co-supervisors at Durham and Newcastle.

Training:

Training will be given in basic microbiology, microbial genetics and physiology, molecular biology, and recombinant protein expression and purification. The project will make use of cryo-electron microscopy and single-particle analysis. This project would suit a candidate with a degree in microbiology, biochemistry, or chemistry. You will also have the opportunity for a 3-month industrial placement.

Informal enquiries may be made to

HOW TO APPLY 

Applications should be made by emailing 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 Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to , 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.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

A. Dissecting the structural and functional roles of a putative metal entry site in encapsulated ferritins. J Biol Chem. (2020).
B. Conservation of the structural and functional architecture of encapsulated ferritins in bacteria and archaea. Biochem. J. 476, 975–989 (2019).
C. Structural characterization of encapsulated ferritin provides insight into iron storage in bacterial nanocompartments. Elife 5, e18972 (2016).
D. Insight into Coenzyme A cofactor binding and the mechanism of acyl-transfer in an acylating aldehyde dehydrogenase from Clostridium phytofermentans. Sci. Rep. 6, 22108 (2016).
E. Interplay between tolerance mechanisms to copper and acid stress in Escherichia coli. Proceedings of the National Academy of Sciences 114(26): 6818–6823 (2017).
F. A genetic screen reveals a periplasmic copper chaperone required for nitrite reductase activity in pathogenic Neisseria. The FASEB Journal 29 (9): 3828-3838 (2015).
G. A role for glutathione in buffering excess intracellular copper in Streptococcus pyogenes. bioRxiv (2020).
H. A superoxide dismutase capable of using iron or manganese promotes the resistance of Staphylococcus aureus to calprotectin and nutritional immunity. PLoS Pathog. 13, e1006125 (2017).
I. An evolutionary path to altered cofactor specificity in a metalloenzyme. Nat Comms 11: 2738 (2020)
J. A four-helix bundle stores copper for methane oxidation. Nature 525: 140-3 (2015).
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