The covalent attachment of the small protein ubiquitin to substrates regulates virtually all cellular processes and its modulation with small molecules is set to revolutionise modern medicine. Central players of the ubiquitin system are E3 ligase enzymes, which catalyse the covalent transfer of ubiquitin to specific substrates.

Our multidisciplinary lab has developed pioneering technologies for E3 ligase discovery and activity measurement ^1,2. The discovery and study of atypical E3 ligases have resulted in new ubiquitin system paradigms with therapeutic opportunities ^3-5. We revealed that MYCBP2 conjugates ubiquitin to atypical sites such as threonine and

uses an unprecedented ubiquitin transfer mechanism we term ubiquitin relay. MYCBP2 promotes programmed axon degeneration so drugs that block its ability to carry out non-lysine ubiquitination have great promise for treating neurological diseases such as multiple sclerosis, neuropathies and ALS. Current work is on how MYCBP2 recognises and modifies the substrates involved and how its activity is tightly regulated to maintain neuronal homeostasis.

In unpublished work, we have made the striking discovery that the activity of RZ (RNF213/ZNFX1) E3 ligases is coupled to their distinct catalytic domains that bind nucleic acids (ATPases and helicases). This allows their E3 activity to respond to the cellular danger signals of elevated ATP and viral-derived RNA. Our lab is also studying these mechanisms in more detail to gain a molecular-level understanding of how these disparate activities cooperate to achieve innate immunity.

A PhD project is available to join our multidisciplinary lab and work on RCR/RZ E3 ligases using a combination of biochemistry and cryoEM/crystallography. Alternatively, we are continuing to develop new chemical biology techniques and technologies and could offer a project in this area ⁶. Hence, applications from individuals with either a biology or chemistry background are encouraged to apply.

References

1 Pao, K. C. et al. Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation. Nat Chem Biol 12, 324-331 (2016). https://doi.org:10.1038/nchembio.2045

2 Mathur, S., Fletcher, A. J., Branigan, E., Hay, R. T. & Virdee, S. Photocrosslinking Activity-Based Probes for Ubiquitin RING E3 Ligases. Cell Chem Biol 27, 74-82 e76 (2020). https://doi.org:10.1016/j.chembiol.2019.11.013

3 Pao, K. C. et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556, 381-385 (2018). https://doi.org:10.1038/s41586-018-0026-1

4 Mabbitt, P. D. et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. Nat Chem Biol 16, 1227-1236 (2020). https://doi.org:10.1038/s41589-020-0598-6

5 Barnsby-Greer, L. et al. UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nat Struct Mol Biol 31, 351-363 (2024). https://doi.org:10.1038/s41594-023-01192-4

6 Squair, D. R. & Virdee, S. A new dawn beyond lysine ubiquitination. Nat Chem Biol 18, 802-811 (2022). https://doi.org:10.1038/s41589-022-01088-2