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(BBSRC DTP) Mechanism of early steps in protein synthesis by cryoEM imaging of supramolecular complexes


Faculty of Biology, Medicine and Health

About the Project

The aim of this project is to understand the mechanism and control of protein synthesis in eukaryotic cells at the molecular level, particularly focused around the role of the eukaryotic translation initiation factors eIF2, eIF5 and eIF2B [1,2]. Protein synthesis is a multistep process that relies on a dynamic series of protein-protein and protein-RNA interactions necessary to assemble ribosomes, factors, tRNAs and mRNA. This project will use recombinant protein expression systems to purify specific protein complexes and then use electron microscopy techniques (CryoEM) to determine their 3-dimensional structures. Analysis of the structures will provide insight into their critical role in protein synthesis and its control, and relevance to human health and disease. For example, mutations in eIF2B cause a genetically inherited brain disease, while regulation of eIF2B activity is critical for a wide variety of cues, including: nutritional responses, stress, fighting viral infections, and long-term memory [1].

We will build upon our recent analysis of structures determined for complexes formed between the translation factors eIF2 and eIF2B [3]. We have biochemical evidence for multiple modes of interaction between eIF2, eIF5 and eIF2B and aim to define these further. Biochemical and biophysical techniques (such as chemical cross-linking and small angle X-ray scattering (SAXS)) will also be used to monitor the assembly of a various complexes to aid trapping transient complexes for structural analysis. These experiments will allow deeper understanding and provide insight into the structures and functions of these factors, guide future functional experimentation and provide insight into human disorders.

The factor eIF2 is phosphorylated in response to cellular stress and inactivates eIF2B by forming a stable complex--called the integrated stress response. Viruses such as coronavirus and picornavirus have evolved a mechanism to counteract this inactivation by producing a protein that binds to eIF2B and activates it, even in the presence of phosphorylated eIF2[4]. We aim to find out more about these stress-response evading mechanisms.

http://www.manchester.ac.uk/research/Alan.Roseman/
http://www.manchester.ac.uk/research/Graham.Pavitt/
http://www.manchester.ac.uk/research/Clair.Baldock/
https://www.wellcome-matrix.org/people/clair-baldock/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships 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.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1. Pavitt GD* (2018). Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA. e1491. doi: 10.1002/wrna.1491.

2. 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

3. Adomavicius T, Guaita M, Zhou Y, Jennings MD, Latif Z, Roseman AM*, Pavitt GD* (2019) The structural basis of translational control by eIF2 phosphorylation. Nature communications 10, 2136. doi: 10.1038/s41467-019-10167-3

4. Rabouw, H.H., Visser, L.J., Passchier, T.C. et al. Inhibition of the integrated stress response by viral proteins that block p-eIF2–eIF2B association. Nat Microbiol (2020).

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