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Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID

Author

Listed:
  • Suman Shrestha

    (University Health Network
    University of Toronto)

  • Matthew E. R. Maitland

    (University Health Network
    University of Toronto
    University of Toronto)

  • Laili Jing

    (University Health Network
    University of Toronto)

  • Shili Duan

    (University Health Network
    University of Toronto)

  • David Y. Nie

    (University Health Network
    University of Toronto
    University of Toronto)

  • Jonathan St-Germain

    (University Health Network)

  • Michael Kanaris

    (University of Toronto
    University of Toronto)

  • Dalia Barsyte-Lovejoy

    (University of Toronto
    University of Toronto)

  • Cheryl H. Arrowsmith

    (University Health Network
    University of Toronto
    University of Toronto)

  • Brian Raught

    (University Health Network
    University of Toronto)

Abstract

Here we describe ProtacID, a flexible BioID (proximity-dependent biotinylation)-based approach to identify PROTAC-proximal proteins in living cells. ProtacID analysis of VHL- and CRBN-recruiting PROTACs targeting a number of different proteins (localized to chromatin or cellular membranes, and tested across six different human cell lines) demonstrates how this technique can be used to validate PROTAC degradation targets and identify non-productive (i.e. non-degraded) PROTAC-interacting proteins, addressing a critical need in the field of PROTAC development. We also demonstrate that ProtacID can be used to characterize native, endogenous multiprotein complexes without the use of antibodies, or modification of the protein of interest with epitope tags or biotin ligase tagging.

Suggested Citation

  • Suman Shrestha & Matthew E. R. Maitland & Laili Jing & Shili Duan & David Y. Nie & Jonathan St-Germain & Michael Kanaris & Dalia Barsyte-Lovejoy & Cheryl H. Arrowsmith & Brian Raught, 2025. "Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63357-7
    DOI: 10.1038/s41467-025-63357-7
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