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(BBSRC DTP) Structural analysis of translational regulatory complexes in the Integrated stress response


Project Description

Researching mechanisms of regulation of protein synthesis via eIF2 molecular complexes

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]. When dysregulated this can contribute to a range of diseases including the progression of some cancers [2]. The structural analysis of complexes involved in activation and resetting the responses are largely unknown. In this project the student will learn to purify proteins and apply cryoEM analyses to important complexes involved in regulating the ISR.

In our labs we already solved complexes of eIF2 and eIF2B using cryoEM. The student will prepare protein complexes and analyse how protein kinases/phosphatases interact with eIF2. We will interpret the molecular interactions to infer biologically relevant information about the regulation.

https://www.research.manchester.ac.uk/portal/alan.roseman.html
https://www.research.manchester.ac.uk/portal/graham.pavitt.html
https://personalpages.manchester.ac.uk/staff/j.warwicker/

Further information will be available on request


Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

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.

Falletta P, Sanchez-del-Campo L, Chauhan J, Effern M, Kenyon A, Kershaw CJ, Siddaway R, Lisle R, Freter R, Daniels MJ, Lu X, Tüting T, Middleton M, Buffa FM, Willis AE, Pavitt GD, Ze’ev AR, Sauka-Spengler T, Hölzel M, Goding CR* (2017). Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev 31:18-33.

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