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

The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target ofthalidomide and lenalidomide(1), therapeutic agents used in the treatment of haematopoietic malignancies(2-4) 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 remains unknown. Here we report that C-terminal cyclic imides, post-translational modificationsthat arise from intramolecular cyclization ofglutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition ofthe 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 timescalesthroughout 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 regulatory processthat may affect the physiological and therapeutic engagement of CRBN.

Automated summary

This study identifies C-terminal cyclic imides as physiological degrons for the ubiquitin E3 ligase substrate adapter cereblon (CRBN). The addition of these degrons induces CRBN-dependent ubiquitination and degradation of proteins. This discovery has significant implications for understanding the physiological and therapeutic engagement of CRBN.