The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
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Ichikawa, Saki
Flaxman, Hope A.
Xu, Wenqing
Vallavoju, Nandini
Lloyd, Hannah C.
Wang, Binyou
Shen, Dacheng
Pratt, Matthew R.
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https://doi.org/10.1038/s41586-022-05333-5Metadata
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Ichikawa, Saki, Hope A. Flaxman, Wenqing Xu, Nandini Vallavoju, Hannah C. Lloyd, Binyou Wang, Dacheng Shen et al. "The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron." Nature 610, no. 7933 (2022): 775-782. DOI: 10.1038/s41586-022-05333-5Abstract
The E3 ligase substrate adaptor cereblon (CRBN) is a target of thalidomide and lenalidomide,1 which are therapeutic agents used in the treatment of hematopoietic malignancies2-4 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 is unknown. Here, we report that C-terminal cyclic imides, overlooked 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 are substitutes for thalidomide when embedded within bifunctional chemical degraders. Installation 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 novel regulatory process that may impact the physiological function and therapeutic engagement of CRBN.Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376875
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