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Structural studies of eukaryotic protein synthesis factor complexes by Cryo EM

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  • Full or part time
    Prof Pavitt
    Dr Roseman
  • Application Deadline
    Applications accepted all year round

Project Description


Molecular recognition drives almost all biological reactions. G proteins function as molecular switches, controlled by interacting ligands and regulatory partners. In the initiation of protein synthesis the G protein eIF2 is required to bind initiator tRNA to ribosomes. Its GTP/GDP status is controlled by 2 factors eIF2B and eIF5. Phosphorylation of eIF2 at a specific serine residue inhibits eIF2B guanine nucleotide exchange activity by forming a non-productive eIF2:eIF2B complex. This mechanism of translational control is conserved across all studied eukaryotes and is important within diverse settings including developmental, metabolism and long-term memory formation. eIF2 and eIF2B are both large multisubunit complexes, and mutations within these factors cause neurological diseases. This project builds on prior and ongoing studies within the Pavitt and Roseman laboratories and aims to probe the structure and interactions between purified translation factor complexes by cryo electron microscopy. Key questions are: How does eIF2B interact with eIF2 to perform guanine nucleotide exchange? and How are its interactions altered by phosphorylation of eIF2?

The project will involve protein expression and purification, molecular biology, electron microscopy and would suit an individual interested in modern molecular and structural biology.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Almeida RA, Fogli A, Gaillard M, Scheper GC, Boesflug-Tanguy O, Pavitt GD (2013) A yeast purification system for human translation initiation factors eIF2 and eIF2Bε and their use in the diagnosis of CACH/VWM disease PLOS One 8:e53958

Reid PJ, Mohammad-Qureshi SS, Pavitt GD. (2012) Identification of Inter-subunit domain interactions within eukaryotic initiation factor (eIF) 2B, the nucleotide exchange factor for translation initiation. J. Biol. Chem. 287:8275-85

Jennings MD, Pavitt GD (2010). eIF5 has GDI activity necessary for translational control by eIF2a phosphorylation. Nature, 465(7296), 378-381

Roseman AM, Borschukova O, Berriman JA, Wynne SA, Pumpens P, Crowther RA (2012) Structures of hepatitis B virus cores presenting a model epitope and their complexes with antibodies. J Mol Biol 423:63-78.

Roseman AM, Beecher N, Jowitt TA, Berry R, Troilo H, Kammerer RA, Shuttleworth CA, Kielty CM, Baldock C (2011) Collagen VI, conformation of A-domain arrays and microfibril architecture. J Biol Chem 286:40266-40275.

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