New classes of E3 ligases illuminated by chemical probes

Specificity in the ubiquitin system depends on E3 ligases, largely belonging to a handful of families discovered more than a decade ago. However, the last two years brought a quantum leap in the identification and/or mechanistic characterization of eukaryotic ubiquitin ligases, in part through implementation of activity-based chemical probes and cryo-EM. Here, we survey recent discoveries of RING-Cys-Relay, RZ-finger, and neddylated cullin-RING-ARIH RBR E3- E3 ubiquitin ligase mechanisms. These ligases transfer ubiquitin through unprecedented mechanisms- via novel catalytic domains or domain combinations-and collectively modify unconventional amino acids, non-proteinaceous bacterial lipid targets, and structurally diverse substrates recruited to numerous cullin-RING ligases. We anticipate major expansion of the types, features, and mechanisms of E3 ligases will emerge from such chemical and structural approaches in the coming years.

Automated summary

Recent advancements in the identification and mechanistic characterization of ubiquitin ligases in eukaryotes have revealed novel mechanisms and expanded the types of substrates modified by these ligases. Utilization of activity-based chemical probes and cryo-EM has played a significant role in these discoveries.