The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron

Abstract

The 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.