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Protein interactions in cancer regulation (BLUMENSCHEINU16SF)

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  • Full or part time
    Dr Blumenschein
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Our research group uses nuclear magnetic resonance (NMR) spectroscopy to look at protein structures, dynamics and interactions, and their roles in protein function. A main topic of interest is the interactions between proteins involved in tumour growth and progression, with the aim of developing peptidomimetic inhibitors that could be developed for the treatment of cancer. Two examples are the study of the coiled-coil interactions in the Fos-Jun system, in collaboration with Dr Jody Mason (University of Essex) and the interactions of WWP2 with its target systems, in collaboration with Dr Andrew Chantry, (School of Biological Sciences, UEA).

The Fos and Jun families of proteins interact to form the Activator Protein 1 (AP-1), a heterodimeric transcription factor that is responsible for the regulation of a number of key genes. Levels of AP-1 components are raised in a large number of tumours, including tamoxifen-resistant breast tumours. Inhibition of AP-1 inhibits growth of breast cancer cells, suggesting that AP-1 can be a valid therapeutic target. We are studying the determinants of affinity and specificity between the coiled-coil regions of Fos and Jun proteins. Understanding the individual contributions of each residue towards the binding will contribute to the future design of peptide and peptidomimetic antagonists of AP-1.

This PhD project aims to obtain NMR spectra of different variants of the Jun-Fos coiled coil, and determine the structure and dynamics of these semi-rationally designed peptide pairs. Understanding how one protein recognizes and binds another with high specificity is important not only for mapping of protein networks, but also in devising peptide and peptidomimetic antagonists that can mimic natural proteins. The ultimate aim is to sequester one half of AP-1 as a non-functional heterodimer using an orally available peptidomimetic. Achieving this goal will first require understanding the molecular mechanisms of specific protein-protein interactions.

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 http://www.uea.ac.uk/pgresearch/pgrfees.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.

References

i) Julien, O., Mercier, P., Allen, C. N., Fisette, O., Ramos, C. H., Lagüe, P., Blumenschein, T. M. A., and Sykes, B. D. (2011) Is there nascent structure in the intrinsically disordered region of troponin I? Proteins 79, 1240-1250.
ii) de Oliveira, J. F., Sforça, M. L., Blumenschein, T. M. A., Guimarães, B. G., de Oliveira, C. C., Zanchin, N. I. T., and Zeri, A.-C. (2010) Structure, dynamics and RNA interaction analysis of the human SBDS protein, J. Mol. Biol. 396, 1053-1069.
iii) Crooks, R. O., Rao, T. and Mason, J. M. (2011) J. Biol. Chem. 286, 29470–29479.
iv) Worrall, J. A. R. and Mason, J. M. (2011) FEBS J. 278, 663–672.
v) Mason, J. M., Schmitz, M. A., Müller, K. M., and Arndt, K. M. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 8989–8994.

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