E3 ubiquitin ligase complexes select proteins for degradation through the recognition of degrons, specific amino acid sequences that are sufficient to promote ubiquitylation and degradation when embedded in a substrate. Despite major landmarks in the discovery of E3 ligases that recognize protein degrons, the degrons recognized and regulated by the vast majority of the 600 E3 ligases await discovery. We use chemical insights and chemical biology tools to discover the C-terminal cyclic imide, an overlooked post-translational modification, as a degron for the E3 ligase adapter cereblon (CRBN) and study its chemical mimics, thalidomide and lenalidomide, which has opened new directions in E3 ligase biology and novel ligand discovery. CRBN is a conserved protein that was originally discovered in association with normal neurological development in humans. Here I will describe current efforts to understand the chemistry of where, when, and how the C-terminal cyclic imide degron occurs and its biological connection to the physiological function of CRBN.

Chemistry and biology of the C-terminal cyclic imide degron

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