Bidentate Molecular Probes for Hect. E3 Ubiquitin Ligase Biological Function

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Protein ubiquitination represents a post-translational modification that regulates a variety of cellular processes including protein turnover, trafficking, sub-cellular localisation, transcriptional function and DNA repair mechanisms. Ubiquitin conjugation involves a cascade of events catalysed sequentially by E1 (ubiquitin-activating), E2 (ubiquitin conjugating), and E3 (ubiquitin ligase) enzymes. This project will focus on the development of novel bivalent molecular probes to elucidate the biological roles and substrate-specific function of a small well-defined sub-group known as the HECT E3 ubiquitin ligases. Of particular interest will be the NEDD4-like E3 ubiquitin-protein ligases WWP1 and WWP2. The latter binds to SMAD proteins in the TGF- signalling pathway, targeting them for degradation. The combined strengths of the lead applicants in advanced Cell/Molecular Biology and Synthetic Chemistry, together with cross-fertilization of new ideas and disciplines, will facilitate novel approaches to elucidate the dynamics of fundamental protein ubiquitination mechanisms. The use of simple chemical tools to probe the function and importance of individual components of complex biochemical pathways/networks clearly fits within the BBSRC remit. The student will embrace a range of techniques (chemical synthesis, mechanistic enzymology, whole cell studies) to probe the functionality of different ligands at both the cellular and molecular level. This is a subject area relevant to BBSRC research priorities at the Chemistry-Biology interface. The outputs of this project could also lead to the next generation of selective inhibitors of cell growth, which would be of great interest for further study and development to produce improved cancer chemotherapeutics. Supporting research that is likely to have a beneficial impact in terms of knowledge transfer, commercialisation and healthcare benefits) is an increasingly important priority within BBSRC.