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The mechanism of regulation of protein synthesis via eIF2 molecular complexes


Project Description

Control of protein synthesis is critical for normal metabolism, development and responses to stress. One major pathway is called the integrated stress response (ISR) and centres on translational control of the general protein synthesis factor eIF2B via the phosphorylation of eIF2 [1,2]. When dysregulated this can contribute to a range of diseases including the progression of some cancers [3]. The structural analysis of large protein complexes involved in the activation and resetting the ISR are largely unknown. In this project the student will learn to purify proteins, assay activities and apply modern cryo-EM analyses to one or more important complexes involved in regulating the ISR.

Specifically in the ISR there are several protein kinases that phosphorylate eIF2 including PKR, GCN2, PERK and HRI in human cells as well as others found in human parasites and other organisms. Each becomes activated by differing signals and then phosphorylates eIF2 on a conserved serine residue. Similarly there are a range of protein phosphatase complexes that reverse this phosphorylation reaction. Both kinases and phosphatases are targeted by known inhibitors of their action.

The student will make use known information and available methods to purify one or more complex for structural and functional evaluation to provide insight into the function of this important and central stress responsive regulatory pathway.

We will use cryoEM to determine and interpret the molecular interactions between eIF2 and the kinases/phosphases, as well as induced larger molecular rearrangements.

Further information will be available on request

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). On the online application form select 'PhD Structural Biology' to apply for this Project.

References

1. Adomavicius, T., Guaita, M., Jennings, M., Latif, Z. & Zhou, Y, Roseman, A.*, Pavitt, G. D.* (2019). The Structural Basis of Translational Control by eIF2 Phosphorylation. Preprint bioRxiv, 501411 doi: https://doi.org/10.1101/501411
2. Merrick WC*, Pavitt GD* (2018). Protein synthesis initiation in Eukaryotic Cells. In Cold Spring Harbor Perspectives in Biology Translation Mechanisms and Control 10.1101/cshperspect.a033092.
3. Jennings MD, Kershaw CJ, Adomavicius T and Pavitt GD* (2017). Fail-safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes. eLife doi: 10.7554/eLife.24542.
4. Jennings MD, Kershaw CJ, White C, Burgess D, Costello JC, Richardson JP, Zhou Y, Pavitt GD* (2016). eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control. Nucleic Acids Res 44:9698-9709
5. Ramsay, E.P., Collins, R.F., Owens, T.W., Siebert, A., Jones, R.P.O., Wang, T., Roseman, A.M. and Baldock, C. (2016) Structure of human retinoschisin reveals novel insights into retinal-1 adhesion and X-Linked Retinoschisis. Human Molecular Genetics, Oct 23, doi:10.1093/hmg/ddw345

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