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

Saki Ichikawa, Hope A. Flaxman, Wenqing Xu, Nandini Vallavoju, Hannah C. Lloyd, Binyou Wang, Dacheng Shen, Matthew R. Pratt and Christina M. Woo ()
Additional contact information
Saki Ichikawa: Harvard University
Hope A. Flaxman: Harvard University
Wenqing Xu: Harvard University
Nandini Vallavoju: Harvard University
Hannah C. Lloyd: Harvard University
Binyou Wang: University of Southern California
Dacheng Shen: Harvard University
Matthew R. Pratt: University of Southern California
Christina M. Woo: Harvard University

Nature, 2022, vol. 610, issue 7933, 775-782

Abstract: Abstract The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide1, therapeutic agents used in the treatment of haematopoietic malignancies2–4 and as ligands for targeted protein degradation5–7. 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 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 regulatory process that may affect the physiological function and therapeutic engagement of CRBN.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05333-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:610:y:2022:i:7933:d:10.1038_s41586-022-05333-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05333-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().