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Using archaeal models to examine the mechanisms and evolution of protein homeostasis pathways that underlie the processes of aging and neurodegeneration


Project Description

The critical balance between the synthesis, maintenance and turnover of all proteins in a cell is a central requirement for life. Following their synthesis and assembly, proteins are frequently subjected to a variety of potentially harmful influences that may result in partial unfolding events that can ultimately result in misfolded or aggregated forms. The accumulation of these damaged proteins can be toxic for the cell. Indeed, disruption to protein homeostasis is a central feature of many cancers, autoimmune diseases and neurodegenerative disorders and the accumulation of damaged proteins is one of the key factors underlying cellular aging processes.

The latest meta-genomic sequencing studies have identified the Asgard archaeal species as the closest relatives of eukaryotes identified to date. These intriguing organisms appear to express membrane-associated complexes indicative of vesicular trafficking systems that appear consistent with lysosomal protein degradation systems and also possess unequivocal homologues of the ubiquitin-proteasome degradation apparatus. This project will combine the expertise of the Robinson and Allsop laboratories to structurally and biochemically interrogate archaeal homologues of components involved in the key protein homeostasis pathways; the lysosomal and ubiquitin-proteasome degradation systems. A major focus of this project will be to reconstitute thermally stable archaeal homologues of the proteins and complexes that underlie these processes. The project will involve a variety of structural, biochemical and biophysical approaches to further our understanding of these mechanisms. The student will learn a number of experimental techniques including protein expression, the measurement of protein-protein and protein-membrane interactions and perform structural analyses using approaches including protein crystallisation, NMR, electron microscopy and atomic force microscopy. By improving our understanding of the functioning and evolution of these fundamental pathways we will glean new insights into the homologous and fundamental eukaryotic protein homeostasis systems that operate to process and degrade toxic substrates, such as amyloid and tau proteins, in human cells.

For informal enquiries and further discussion of the project please contact Dr Nick Robinson () or Professor David Allsop ().

Applications are made by completing an application for PhD Biomedical and Life Sciences October 2018 through our online application system. Closing date: midnight 28th February 2018.


Funding Notes

Awards are available for UK or EU students only for a maximum of three years full-time study. Awards will cover University Fees and Doctoral Stipend (2018-2019: £14,777).

References

Functional reconstruction of a eukaryotic-like E1/E2/(RING)E3 ubiquitylation cascade from an uncultured archaeon
James, R.H., Caceres, E.F., Escasinas, A., Alhasan, H., Howard, J.A., Deery, M.J., Ettema, T.J.G., Robinson, N.P. 24/10/2017 In: Nature Communications. 8, 15 p.

Involvement of a eukaryotic-like ubiquitin-related modifier in the proteasome pathway of the archaeon Sulfolobus acidocaldarius
Anjum, R.S., Bray, S.M., Blackwood, J.K., Kilkenny, M.L., Coelho, M.A., Foster, B.M., Li, S., Howard, J.A., Pellegrini, L., Albers, S., Deery, M.J., Robinson, N.P. 8/09/2015 In: Nature Communications. 6, 15 p.

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