Diamond Light Source PhD Studentship: Structural Biology of Complex Enzymes in Parkinson’s Disease

University of Reading - Systems Pharmacology of Macroautophagy in Parkinson’s Disease

Project title:  Structural and Functional Characterisation of Human ROCO Proteins – How Multi-domain Proteins Work to Integrate Intracellular Signalling Pathways

Department/School: Pharmacy/SCFP

Supervisors: Patrick Lewis (University of Reading), Martin Walsh (Diamond Light Source) and Maud Dumoux (Diamond Light Source)

Project Overview: In 2003, the Ras of complex proteins (ROCO) proteins were identified as large multi-domain proteins and have been the subject of intense scrutiny, resulting from their association with a number of human diseases including Parkinson’s and cancer. ROCO proteins are unique in the human proteome as they are the only proteins to pair a GTPase domain with a kinase domain in the same open reading frame. As both are key enzymatic domains involved in cell signalling, it is likely that ROCO proteins act as cellular signal transduction hubs. To date, much of the research of the human ROCO proteins has been limited to LRRK2, as a key player in Parkinson’s disease, but a general understanding is still lacking. However, ROCO proteins are being actively investigated as potential therapeutic targets for human disease – emphasising the importance of generating structural data for this family of proteins.

The aim of this project is to understand how the ROCO proteins integrate cell-signalling pathways at a structural level, using human ROCO proteins including LRRK2, LRRK1 and DAPK1 as models. To achieve this, a multi-construct multi-host strategy will be adopted to produce full-length and combinations of protein domains prior to structural analysis by crystallography and/or cryo-EM analysis. Analysis of structural dynamics will be supported by a range of techniques including Synchrotron Radiation Circular Dichroism (SR-CD), X-ray diffraction, cryoEM and solution scattering at Diamond Light Source. Additionally, built on the Lewis’ group experience, functional mutations will be generated for assays to systematically assess the role/impact of these on activity. In parallel, the constructs will be used for cell biology assays to identify and characterise functional interactions based at the University of Reading.


  • Applicants should hold or expect to gain a minimum of a 2:1 Bachelor Degree or equivalent in Biochemistry, Chemistry or a related subject
  • Due to restrictions on the funding this studentship is open to UK/EU students.

Funding Details:

  • Starts 09/2018
  • Four year award
  • Tuition fees plus stipend at Diamond Light Source rate (starting stipend £16,772)

How to apply:

To apply for this studentship please submit an application for a PhD in Pharmacy at www.reading.ac.uk/graduateschool/prospectivestudents/gs-how-to-apply.aspx.

*Important notes*

  • 1) Please quote the reference ‘GS18-026’ in the ‘Scholarships applied for’ box which appears within the Funding Section of your on-line application.
  • 2) When you are prompted to upload a research proposal, please omit this step.

Further Enquiries:

Please note that, where a candidate is successful in being awarded funding, this will be confirmed via a formal studentship award letter; this will be provided separately from any Offer of Admission and will be subject to standard checks for eligibility and other criteria.

For further details please contact Dr Lewis (p.a.lewis@reading.ac.uk) or Dr Dumoux (maud.dumoux@diamond.ac.uk)

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