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

Author

Listed:
  • 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
    University of Southern California)

  • Christina M. Woo

    (Harvard University)

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.

Suggested Citation

  • Saki Ichikawa & Hope A. Flaxman & Wenqing Xu & Nandini Vallavoju & Hannah C. Lloyd & Binyou Wang & Dacheng Shen & Matthew R. Pratt & Christina M. Woo, 2022. "The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron," Nature, Nature, vol. 610(7933), pages 775-782, October.
    • Handle: RePEc:nat:nature:v:610:y:2022:i:7933:d:10.1038_s41586-022-05333-5
    DOI: 10.1038/s41586-022-05333-5
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    Cited by:

    1. Ka-Yiu Edwin Kong & Susmitha Shankar & Frank Rühle & Anton Khmelinskii, 2023. "Orphan quality control by an SCF ubiquitin ligase directed to pervasive C-degrons," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Gang Xue & Jianing Xie & Matthias Hinterndorfer & Marko Cigler & Lara Dötsch & Hana Imrichova & Philipp Lampe & Xiufen Cheng & Soheila Rezaei Adariani & Georg E. Winter & Herbert Waldmann, 2023. "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Alena Kroupova & Valentina A. Spiteri & Zoe J. Rutter & Hirotake Furihata & Darren Darren & Sarath Ramachandran & Sohini Chakraborti & Kevin Haubrich & Julie Pethe & Denzel Gonzales & Andre J. Wijaya , 2024. "Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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