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

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.