Decoding ubiquitin ligase structure and substrate selectivity (CHANTRY_U16WDTP) Decoding ubiquitin ligase structure and substrate selectivity (CHANTRY_U16WDTP)

Primary Supervisor: Dr Andrew Chantry (,

Project Description

Ubiquitin modification of specific substrates represents an important regulatory mechanism controlling many cellular processes including protein turnover, sub-cellular localisation, transcription and DNA repair. E3 ubiquitin (Ub) ligases are responsible for the final step of ubiquitin transfer, and commonly each Ub ligase is able to target several distinct substrate proteins. However, the choice and preference for recruitment of individual E3 ligase substrates is poorly understood. Our focus in this project will be on a small sub-group of so-called Nedd4 E3 Ub ligases, and primarily the WWP2 Ub ligase, which also plays a key role in development and disease. WWP2 has a unique structural organization that includes four WW domains that specifically select target substrates. The specific objectives of this proposal will be to establish the cellular and molecular details of the interactions of individual and tandem WWP2 domains in WWP2 with their target sequences in it’s main target substrates PTEN, Oct4, Smads and Notch3-ICD, in order to fully understand the biological roles and significance. The experimental approach will include protein expression and structure determination by NMR or X-ray crystallography, binding site mapping, and detailed biophysical characterisation of binding affinities and interaction interfaces. The project will provide an excellent training platform for a PhD student to gain a wide-range of multi-faceted skills relevant to the study of normal and disease-specific biology. Combined strengths within well-funded research laboratories, together with cross-fertilization of new ideas and disciplines, will provide an excellent training platform for a PhD student relevant to elucidating the dynamics of fundamental cellular ubiquitinylation mechanisms.

This project has been shortlisted for funding by the Norwich Biosciences Doctoral Training Partnership (NRPDTP). Applicants shortlisted for the Second Round of Selection (deadline for applications 26th February 2016) will be interviewed as part of the studentship competition on either the 16th or 17th March 2016.

The Norwich Biosciences Doctoral Training Partnership (NRPDTP) offers postgraduates the opportunity to undertake a 4 year research project whilst enhancing professional development and research skills through a comprehensive training programme. You will join a vibrant community of world-leading researchers. All NRPDTP students undertake a three month professional internship (PIPS) during their study. The internship offers exciting and invaluable work experience designed to enhance professional development. Full support and advice will be provided by our Professional Internship team. Students with, or expecting to attain, at least an upper second class honours degree, or equivalent, are invited to apply.

Start date: October 2016
Programme: PhD
Mode of Study: Full Time
Entry Requirements: Acceptable First Degree: Minimum Entry Standard: 2:1

For further information and to apply, please visit our website: