Expanding the ligandable E3 ubiquitin ligases for targeted protein degradation

Out of more than 600 E3 ubiquitin ligases in cells, currently only a handful have small molecule binders that can be used for PROteolysis Targeting Chimeras (PROTACs) and harnessed for targeted protein degradation. PROTACs are bivalent small molecules, i.e. they contain two moieties: one binds a target protein and the other binds an E3 ubiquitin ligase, which marks the target protein for destruction. In this way, PROTACs can bring two proteins that naturally do not interact with each other into proximity. With the new-found proximity, the E3 ligase can put ubiquitin on its new neighbour, thereby marking it for degradation by the cellular protein waste disposal machinery called the proteasome.

PROTAC-mediated degradation of target proteins is a new approach of targeting disease-relevant proteins that are difficult to target with conventional drugs or small molecules. Therefore, the development of PROTACs is a rapidly growing area of research. Additionally, not every E3 ligase can target every protein recruited via PROTACs for degradation, and there have been reports of cancer cells developing a resistance to PROTACs via mutations in E3 ligases. Therefore, the expansion of the PROTAC toolbox by identification and inclusion of novel E3 ligase recruiting molecules is an important and critical step in targeted protein degradation.

With this project, we seek to identify short protein sequences (peptides) capable of recruiting E3 ligases, determine the molecular mechanisms of the interactions and exploit the findings for potential use in novel PROTAC development. We have already analysed several novel E3 ligases for their ability to degrade different target proteins and have found a set of four E3 ligases which can efficiently target proteins in different subcellular locations.

The aim now to identify natural interactors or substrates of these E3 ligases by interaction studies and narrow down the shortest part of the interacting proteins needed for this interaction. From this, a common sequence with high affinity towards the respective E3 ligase would be determined, and in turn exploited for proximity-driven target protein degradation using the Affinity-directed PROtein Missile (AdPROM) system that our lab has developed. If validated, the peptide binders will be taken further to develop potential warheads of E3 ligases to use in PROTAC molecules.

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