We use biochemical, structural and cell biology techniques to study how the small protein modifier Ubiquitin regulates the fate and function of proteins. Through this fundamental knowledge, we aim to develop new ways to develop Targeted Protein Degradation modalities for human disorders including neurodegenerative diseases and cancer.

The synthesis and degradation of proteins must be tightly coordinated to ensure only the necessary proteins are present in cells at exactly the right time when they are needed. An imbalance in either of these processes can lead to the accumulation of proteins in the form of aggregates which can then impair essential cellular functions. Fibrils and tangles are examples of protein aggregation which are often detected in neurodegenerative disorders. In eukaryotes, proteins destined for degradation must first be tagged with ubiquitin prior to being turned over by either to the proteasome, if the protein is cytosolic, or through the lysosomal pathway in the case of extracellular molecules and some membrane receptors. Larger intracellular cargoes, including large macromolecular complexes and organelles, are cleared and recycled through the autophagy-lysosomal pathway. Ubiquitin can exist as polymers on proteins, so called ubiquitin chains, which can be assembled through 8 different attachment points on ubiquitin. A plethora of ubiquitin chains can therefore be assembled, and these have different impact on the fate and function of proteins. Determining how enzymes which add (E3 ubiquitin ligase) and remove ubiquitin (deubiquitylase) function is important to better understand how protein fate and function is regulated at the molecular and cellular level.

Our worked has so far focused on the deubiquitylating enzyme TRABID which we have shown makes a unique type of ubiquitin chain assembled through K29 and K33-linked ubiquitin (Licchesi et al, 2011, Nature Structural Biology). We explored new ways including activity-based probes to study HECT E3 ubiquitin ligase (Byrne et al, 2017, ChemBiochem) and have also determined that the E3 ubiquitin ligase HECTD1 assembles a unique type of ubiquitin chains, namely branched K29/K48 chains (Harris et al, 2020, Journal Biological Chemistry). Importantly, this work identified TRABID-HECTD1 as the first DUB-E3 pair regulating ubiquitin chains assembled via K29. Through collaboration with John Burke (Victoria, Canada), EMBL Hamburg, Christiane Berger-Schaffitzel (University of Bristol) we are carrying structure-function studies to identify the molecular determinants which confer HECTD1 its unique enzymatic activity/specificity. We have recently shown that HECTD1 depletion in cells reduces cell proliferation through an effect on mitosis (Vaughan et al, 2021, BioRxiv) and we are also exploring the regulation of HECTD1 in mammalian (Scholz et al, In preparation) and neuronal cells (Jasem et al, In preparation, collaboration with Rob Williams, University of Bath). In collaboration with Florian Siebzehnrubl (Cardiff University) we are also exploring the role of HECTD1 in Glioblastoma (Scholz et al 2020, Frontiers in Oncology).

Building on our significant expertise in ubiquitin biology, we are also developing new modalities for Targeted Protein Degradation (TPD). TPD is revolutionising the pharmaceutical industry by providing new approaches for targeting proteins for degradation including the “undruggable proteome” which refers to 85% of the proteome which currently cannot be targeted by conventional therapeutics.

I have supervised 5 PhD students, three have submitted and completed their thesis within 4 years, 1 is on track to submit within 4 years and 1 student exited with an MRes. PhD alumni students from my lab are now working as Patent Attorney, Manufacturing Scientist at BioRad Laboratories or as Lecturer at Kuwait University.

The lab currently has openings for students who could self-fund through government scolarships. Projects in the lab include: Structure-function studies of E3 ubiquitin ligases; Developping new modalities for Targeted Protein Degradation; Exploring the role of HECTD1 ligases in cell signalling; Identifying new ubiquitin enzymes in pathogenic bacteria.

Please get in touch if you are interested.