The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
Open accessAbstract
The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide 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 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.
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The underlying principles of molecular glue mechanisms might be rooted in partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions further enhanced by a matching molecular glue.
“Taken together, our findings provide another example that the underlying principles of molecular glue mechanisms might be rooted in the partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions that are further enhanced by a matching molecular glue1,10,11,50–54.”
From Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry (2026) · cites this paper as [10]
In “Cyclic imides are substrates for CRBN” (page not supplied), the paper shows that a naturally occurring degron can substitute for thalidomide in CRBN-dependent degraders, supporting a specific example of molecular mimicry. It does not establish that molecular glues generally act at sites of high preexisting protein–protein interaction propensity or enhance those natural interactions. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThis finding hints at a connection between acetylation and the C-terminal cyclic glutarimide degrons favored by CRBN.
“This finding hints at a connection between acetylation and the C-terminal cyclic glutarimide degrons favored by CRBN [63].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [63]
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“In contrast, the CULT domain appears critical for native and drug-induced CRBN functions, as it harbors the tritryptophan pocket (Trp-cage) that engages cyclic imide degrons 10,11 , as well as its small-molecule mimetic, the glutarimide moiety of lenalidomide-type MGDs 16–18 .”
- Authors
- Ichikawa, S., Flaxman, H. A., Xu, W., Vallavoju, N., Lloyd, H. C., Wang, B., Shen, D., Pratt, M. R., & Woo, C. M.
- Affiliations
- Harvard University (US)
- University of Southern California (US)
- Corresponding author
- Woo, Christina M.
- ORCID
- Venue
- Nature
- Published
- 2022-10-19
- Volume
- 610
- Issue
- 7933
- Pages
- 775-782
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10316063
- OpenAlex
- W4306810360
- Cited by
- 195
- References
- 57
- Citations by year
- 2026: 38 · 2025: 73 · 2024: 50 · 2023: 32 · 2022: 2
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- Camille and Henry Dreyfus Foundation
- Bristol-Myers Squibb
- Harvard University
- Ono Pharma Foundation
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Cancer Institute
- National Institute of General Medical Sciences (R01GM114537)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- cereblon, E3 ubiquitin ligase, targeted protein degradation, thalidomide, lenalidomide, ubiquitination, protein degradation, post-translational modification, hematologic malignancies
- MeSH terms
- Lenalidomide, Asparagine, Cyclization, Dipeptides, Glutamine, Humans, Imides, Ligands, Peptide Hydrolases, Thalidomide, Proteome, Amino Acid Motifs, Ubiquitin-Protein Ligase Complexes, Ubiquitination, Proteolysis
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