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

ABSTRACT: The E3 ligase factor cereblon (CRBN) is a target of thalidomide and lenalidomide, which are therapeutic agents used in the treatment of hematopoietic malignancies and as ligands for targeted protein degradation. 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, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are degrons for CRBN. Dipeptides bearing the cyclic imide degron are substitutes for thalidomide when embedded within bifunctional small molecule degraders. Installation of the degron to the C-terminus of proteins induces CRBN-dependent ubiquitylation and degradation in vitro and in cells. C-Terminal cyclic imides are previously underappreciated post-translational modifications found throughout the human proteome that are endogenously recognized and removed by CRBN. The discovery of the cyclic imide degron defines a novel regulatory process controlled by these modifications, which may impact the development of therapeutic agents that engage CRBN.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Erythrocyte, Cell Suspension Culture, Blood Cell, Cell Culture, Blood

SUBMITTER: Christina Woo  

LAB HEAD: Christina Woo

PROVIDER: PXD034248 | Pride | 2022-07-28

REPOSITORIES: Pride