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Structure and Mechanism in a Protein Interaction System Controlling Transcriptional Responses in Neurons


Department of Chemistry

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Prof A J Wilkinson , Dr S Sweeney No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The transcription factor, Activator Protein-1 (AP-1), is a dimer composed of two proteins, Fos and Jun. AP-1 is the primary mediator of protective transcriptional responses of neurons to reactive oxygen species (ROS). ROS are a major factor in neurodegeneration, since they cause damage to lipids, proteins and DNA in neuronal cells which carry a high metabolic burden. At low levels, ROS have a normal physiological role in neuronal activity. Regulation and activation of AP-1 in neurons in response to ROS, at basal and pathological levels, is poorly understood. We have recently identified ROS-dependent binding of AP-1 to the enzyme, GTP-cyclohydrolase 1 (GCH1). GCH1 catalyses the rate-limiting step in the synthesis of the ROS sensitive co-factor, tetrahydrobiopterin (BH4). High levels of BH4 inhibit GCH1 activity by a classical feedback mechanism. We find AP-1 binds to GCH1 in a ROS and BH4-dependent manner linking BH4 levels to the protective AP-1 response in a rheostat-type mechanism. As part of this DTP studentship, we plan to characterise, using structural and biophysical/biochemical methods, interactions among the components of this protective mechanism in neurons. We have generated soluble recombinant heterodimers of Fos/Jun and the future plan is to determine the structure of this critical transcription factor using X-ray crystallography. Subsequently, we will measure the stoichiometry and stability of complexes formed by AP-1, BH4 and GCH1 as a prelude to structure determination using a combination X-ray crystallography and cryo-electron microscopy. The work will illuminate an important ROS protective mechanism in neurons and have implications for our understanding of ageing and age-related disease.

All Chemistry research students also 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 White Rose DTP in Mechanistic Biology is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

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%) unless you require a student visa to study in the UK when you should check the restrictions of your visa as it is very likely you will have to study full time.

This PhD will formally start on 1 October 2021. Induction activities will start on 27 September.

For more information about the project, click on the supervisor’s name above to email the supervisor. For more information about the application process or funding, please click on email institution

Funding Notes

This project is part of the BBSRC White Rose Doctoral Training Programme in Mechanistic Biology. Appointed candidates will be fully-funded for 4 years. The funding includes:

Tax-free annual UKRI stipend (£15,285 full time for 2020/21)
UK tuition fees (£4,473 for 2021/22)
Research support and training charges (RSTC)

International candidates (including EU) will be considered however the fee difference would need to be covered from other sources. International tuition fees for 2021 entry is £22,250.

Not all projects will be funded; a limited number of strong candidates will be appointed via a competitive process.

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 programme 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. If English is not your first language, you will need to meet the minimum entry requirements for your country. Please check our website: https://www.york.ac.uk/study/postgraduate-research/apply/international/english/

HOW TO APPLY: Submit an application for a PhD in Biological Chemistry: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPBIOSCHE4
If you are applying for more than one PhD in Biological Chemistry project you do not need to submit separate applications but can list them on the same form. However, if you are applying for a PhD in Chemistry or a PhD in Mechanistic Biology, you will need to submit a separate application
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