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

ABSTRACT: The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide¹, 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 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 substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to t

SUBMITTER: Ichikawa S 

PROVIDER: S-EPMC10316063 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature