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Poster Presentations
Day 3, June 24（Tue.）
Room P (Maesato East, Foyer, Ocean Wing)
- 3P-PM-41（2C-O2-1440）
Proteome-Wide Degron Screening
(1UNSW, 2UTS)
oJake Violi1, Suhyeon Kwon1, Priyanka Kundu1, Connor Phillips2, William Donald1
E3 ligases are a family of proteins part of the three-step enzymatic cascade involved in the transfer of ubiquitin to a target protein. Ubiquitination regulates many cellular processes namely protein degradation. E3s recognise structural motifs known as degrons allowing for interactions between an E3 ligase and a target protein. Some degrons have weak E3 affinities; molecular glues (MGs) function by stabilizing weak, pre-existing interactions between E3 ligases and their substrates, effectively redirecting ubiquitination pathways for targeted protein degradation. This allows for a new avenue of treatment for many diseases such as cancer, manipulating the ubiquitin system to target proteins integral to the pathology of these diseases. Despite their promise, only two major classes of MGs, immunomodulatory imide drugs (IMiDs) and RBM39 degraders, have been discovered, both serendipitously. To address this, we developed a mass spectrometry-based approach that integrates affinity selection mass spectrometry (AS-MS) with native mass spectrometry (nMS) to systematically identify degron–E3 ligase interactions. This pipeline enables the direct screening of proteomic digests to detect transient, low-affinity substrate interactions that could be exploited for MG enhancement. Application of this workflow to multiple E3 ligases revealed both known and novel degron motifs, significantly expanding the landscape of potential MG targets.