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(BBSRC DTP) Towards artificial signal transduction in living cells

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  • Full or part time
    Dr S Webb
    Dr J Gough
    Dr A Green
    Prof N Turner
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The development of synthetic molecules able to transmit biochemical information across phospholipid bilayers could lead to a new type of synthetic biology, where the introduction of orthogonal signalling pathways leads to ‘short-circuiting’ of natural signalling networks in cells. G-protein-coupled receptors (GPCRs) are a key class of membrane protein that mediates cellular signal transduction, doing so through external ligand-induced conformational changes in helical transmembrane domains, which then triggers enzymatic cascades in the cell.

Foldamers (folded oligomers) comprising α-aminoisobutyric acid (Aib) have particular promise as mimics of GPCR function. These oligomers, which fold into extended 310 helices, have a conformation that is very sensitive to binding events at their N-terminus. For example adenosine complexation to a boronate-capped Aib foldamer in solution caused a conformational switch that was relayed to a reporter group at the far terminus, > 2 nm distant.1 We have also developed light-switchable Aib foldamers able to relay photochemical information over similar distances within phospholipid bilayers, in a manner reminiscent of the light-sensitive GPCR, rhodopsin.2 Most recently we developed a foldamer that mimics the behaviour of other GPCRs, transmitting binding information from an external ligand(Leu enkephalin) several nanometres into a bilayer.3

In this project, we will apply these promising biomimetic systems in a cellular context. Synthetic signal transducers (foldamers) that bear new fluorescent reporter groups will be chemically synthesised, which will be followed by studies of foldamer conformation and helicity switching in the membranes of living cells (fibroblasts). The signalling mechanism will be then linked to enzymatic activity, with a series of proteases and esterases used to transform non-binding or non-active signals into signalling molecules. If successful, this project may produce a synthetic link between exterior biocatalytic reactions and metabolism inside living cells.

Qualification
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.

Contact for further Information
For more details contact Dr Simon Webb ([email protected])

www.webblab.org
http://personalpages.manchester.ac.uk/staff/j.gough/
https://www.research.manchester.ac.uk/portal/anthony.green.html

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 www.manchester.ac.uk/bbsrcdtpstudentships

References

[1] Brown, R. A.; Diemer, V.; Webb, S. J.; Clayden, J. Nature Chem. 2013, 5, 853.
[2] De Poli, M.;Zawodny, W.; Quinonero, O.; Lorch, M.; Webb, S.J.; Clayden, J. Science 2016, 352, 575.
[3] Lister, F. G. A.; Le Bailly, B. A. F.; Webb, S. J.; Clayden, J. Nature Chem. 2017, 9, 420.

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