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Identification of the Trypanosoma brucei transferrin receptor-recognition site of transferrin (SteverdingDU19SF)


Project Description

The transferrin receptor of the protozoan parasite Trypanosoma brucei (TbTfR) is a heterodimeric protein complex encoded by two expression site associated genes, ESAG6 and ESAG7, which shows no homology to the homodimeric human transferrin receptor (hTfR). Binding of one molecule of transferrin (Tf) requires association of both ESAG6 and ESAG7 as was shown by co-expression in heterologous systems. Tf is a monomeric glycoprotein with two structurally similar domains called the N- and C-lobes. The C-lobe forms a well-characterised primary recognition site for the hTfR. The domain of Tf that is recognised by the TbTfR remains unknown. However, this domain represents an important host-pathogen interface and an understanding of the protein-protein interactions at molecular level will provide a therapeutic opportunity for the design of agents able to produce selective blockade of iron uptake into the parasite, but at the same time having little effect on iron uptake by the host.

Objectives of the PhD

The overall aim of this project is to determine the host-pathogen interface between Tf and the TbTfR at the molecular level and to show that blockage of this interaction is detrimental to the growth of T. brucei. The individual measurable objectives are:

(i) to identify the part of Tf that interacts with the TbTfR by crystal structural analysis of the receptor-ligand complex,

(ii) to design peptides that are able to interfere with the binding of Tf to the TbTfR, and

(iii) to test the peptides for inhibiting the growth of trypanosomes.

For more information on the supervisor, please go here: https://www.uea.ac.uk/medicine/people/profile/d-steverding

This is a PhD programme.

The start date of the project is either 1 April or 1 July 2020.

The mode of study is full-time. The studentship length is 4 years (3 years period of study, 1 year period of registration).

Please note: Applications are processed as soon as they are received and the project may be filled before the closing date, so early application is encouraged.

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at View Website

Entry requirements:

Acceptable first degree in Biology, Biochemistry, Microbiology, Parasitology, Molecular Biology, Cell Biology, Biological Science, Biomedical Science, Medical Science, Infectious Disease, Medicinal and Biological Chemistry, Chemistry.

The standard minimum entry requirement is 2:1.

References

i) Steverding, D., Stierhof, Y.-D., Chaudhri, M., Ligtenberg, M., Schell, D., Beck-Sickinger, A.G. & Overath, P. (1994) ESAG 6 and 7 products of Trypanosoma brucei form a transferrin binding protein complex. Eur. J. Cell Biol. 64, 78-87.

ii) Steverding, D., Stierhof, Y.-D., Fuchs, H., Tauber, R. & Overath P. (1995) Transferrin binding protein complex is the receptor for transferrin uptake in Trypanosoma brucei. J. Cell Biol. 131, 1173-1182.

iii) Steverding, D. (1998) Bloodstream forms of Trypanosoma brucei require only small amounts of iron for growth. Parasitol. Res. 84, 59-62.

iv) Steverding, D. (2000) The transferrin receptor of Trypanosoma brucei. Parasitol. Int. 48, 191-198.

v) Steverding, D., Sexton, D.W., Chrysochoidi, N. & Cao, F. (2012) Trypanosoma brucei transferrin receptor can bind C-lobe and N-lobe fragments of transferrin. Mol. Biochem. Parasitol. 185, 99-105

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