Ichikawa, SakiFlaxman, Hope A.Xu, WenqingVallavoju, NandiniLloyd, Hannah C.Wang, BinyouShen, DachengPratt, Matthew R.Woo, Christina2023-08-212022-10-19Ichikawa, Saki, Hope A. Flaxman, Wenqing Xu, Nandini Vallavoju, Hannah C. Lloyd, Binyou Wang, Dacheng Shen et al. "The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron." Nature 610, no. 7933 (2022): 775-782. DOI: 10.1038/s41586-022-05333-50028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376875The E3 ligase substrate adaptor cereblon (CRBN) is a target of thalidomide and lenalidomide,1 which are therapeutic agents used in the treatment of hematopoietic malignancies2-4 and as ligands for targeted protein degradation.5-7 These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN is unknown. Here, we report that C-terminal cyclic imides, overlooked post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron are substitutes for thalidomide when embedded within bifunctional chemical degraders. Installation of the degron to the C-terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-Terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a novel regulatory process that may impact the physiological function and therapeutic engagement of CRBN.en-USMultidisciplinaryJournal Article2023-08-2110.1038/s41586-022-05333-5