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(BBSRC DTP CASE) Biophysical characterisation and design of optogenetic control elements

  • Full or part time
  • Application Deadline
    Friday, January 31, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Inducible gene ‘switches’ are a core technology in synthetic biology that enable at-will gene expression and the programming of cellular function. Optogenetics makes use of light-controlled inducers and allows unparalleled temporal and spatial control of either gene expression or repression. A current focus of optogenetics is the development of systems that respond to different wavelengths of light, ‘multichromic control’, potentially allowing multiple control elements within a single cell; e.g. individually responding to blue, green and red light. However, until recently, green light inducers were lacking. The discovery and subsequent development of a construct containing coenzyme B12-dependent CarH, which responds to green light, now plugs this gap. However, the in vitro biophysical characterisation of these CarH constructs (they are chimeric fusion proteins) is limited, which limits the improvement and extension of this system for use in optogenetics and synthetic biology. This project will use a range of biophysical techniques to investigate the mechanism of CarH-based optogenetic constructs. It will make use of (light-activated) time-resolved spectroscopy – both optical and mass spectrometry based – to characterise coenzyme B12 binding and the light-dependence of the protein oligomeric state, which is functionally relevant. Mutagenesis and construction of new chimeric proteins will be used to both investigate mechanism and develop systems with improved or altered activity.

The PhD student will be based in Department of Chemistry and the Manchester Institute of Biotechnology (MIB) and will be co-supervised by Dr Sam Hay and Professor Perdita Barran, with additional technical support and supervision from Senior Experimental Officer Dr Derren Heyes. Overall, the work will provide a highly interdisciplinary approach to (bio)chemistry/ biophysics-based research, offering highly diverse training opportunities to a PhD student. The Manchester-based supervisors have long-established collaborations with the industrial partner at the National Physical Laboratory (NPL) and the student will have the additional benefit of being able to access the local supervisors’ laboratories on a daily basis, as they are co-located within the same building (MIB).

http://www.research.manchester.ac.uk/portal/Sam.Hay.html
http://www.research.manchester.ac.uk/portal/Perdita.Barran.html
npl.co.uk/people/alex-jones

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 Partnership. 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

1. A Green-Light-Responsive System for the Control of Transgene Expression in Mammalian and Plant Cells (2018). Chatelle,…,AR Jones, … et al. (2018) ACS Synthetic Biology, 7, 1349
2. Atomic description of an enzyme reaction dependent on reversible 1,3-dipolar cycloaddition. Bailey et al, Hay and Leys. Nature Chemistry, in press; DOI: 10.1038/s41557-019-0324-8
3. Equatorial Active Site Compaction and Electrostatic Reorganization in Catechol-O-methyltransferase (2019). S Czarnota, LO Johannissen, NJ Baxter, F Rummel, AL Wilson, MJ Cliff, CW Levy, NS Scrutton, JP Waltho, S Hay, ACS Catalysis 9, 4394-4401
4. Native mass spectrometry reveals the conformational diversity of the UVR8 photoreceptor (2019) IS Camacho,A Theisen, LO Johannissen, LA Díaz-Ramos, JM Christie, GI Jenkins, B Bellina, P Barran, AR Jones, Natl Acad Sci U S A. 116, 1116-1125
5. The photochemical mechanism of a B12-dependent photoreceptor protein (2015). RJ Kutta, SJO Hardman, LO Johannissen, B Bellina, HL Messiha, JM Ortiz-Guerrero, M Elías-Arnanz, S Padmanabhan, P Barran, NS Scrutton, AR Jones Nature Commun. 12, 7907-

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