E3 ligases are a startling class of enzyme that attach the small protein ubiquitin to substrates and regulate virtually all aspects of the cell. To ensure their activity is kept in check, it is subject to strict regulation and when this goes awry it can lead to diseases such as cancer, neurodegeneration and autoimmunity. The regulatory mechanisms for the ~700 E3s are only understood for a handful of members yet exciting and unexpected mechanisms remain to be discovered. This project will gain a molecular level understanding of how E3s associated with disease become activated and how mutations affect their ability to do so. This will provide insights into the causes of diseases and how they might be treated. This is multidisciplinary project that will make use of powerful chemical probes developed by the lab and combine with techniques ranging from cell biology to structural biology, depending on experience.

References:

Life Sci Alliance. 2022, 5:e202101248.

BioRxiv 2020.05.11.087965; doi: https://doi.org/10.1101/2020.05.11.087965

Nature Chemical Biology 2016, 12 (5), 324.