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Regulating oxidative stress protection in neurons: structural studies of a signal integration system


Project Description

This project has at its heart the structure and interactions of three proteins and a small molecule that regulate the response of neurons
to oxidative stress. Fos and Jun, form a heterodimer that activates the transcription of oxidative stress response genes. GTP cyclohydrolase catalyses the biosynthesis of tetrahydrobiopterin, BH4, a metabolite that scavenges reactive oxygen species (ROS) so preventing damage to the cell. It is also an allosteric regulator of GTP cyclohydrolase; thus BH4 regulates its own synthesis. We have discovered a BH4-dependent regulatory interaction between Fos-Jun and GTP cyclohydrolase. Thus, under normal conditions Fos-Jun is sequestered in an inhibitory complex with GTP cyclohydrolase. Upon encountering ROS, BH4 levels fall and Fos-Jun is released to switch on the transcriptional response to oxidative stress.

Here we will produce and purify recombinant proteins whose interactions will be analysed using biophysical techniques. For protein
structure determination, crystals will be grown and tested in-house in anticipation of 3D data collection at a synchrotron. As GTP
cyclohydrolase is a decamer, the structure of this enzyme and its complexes may be approached by cryo-electron microscopy using
facilities being set up in York. Together, these experiments should reveal the structural basis of this intriguing stress response.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.

Funding Notes

This is a BBSRC White Rose DTP studentship fully funded for four years and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 estimated for 2020 entry), (ii) research costs, and (iii) tuition fees at the UK/EU rate.

It is available to those who are eligible for research council studentships: View Website

References

Entry requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this research project means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.

Related Subjects

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

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