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A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues

Author

Listed:
  • Satoshi Yamanaka

    (Ehime University)

  • Yuto Horiuchi

    (Ehime University)

  • Saya Matsuoka

    (Ehime University)

  • Kohki Kido

    (Ehime University)

  • Kohei Nishino

    (Tokushima University)

  • Mayaka Maeno

    (Nagoya Institute of Technology)

  • Norio Shibata

    (Nagoya Institute of Technology)

  • Hidetaka Kosako

    (Tokushima University)

  • Tatsuya Sawasaki

    (Ehime University)

Abstract

Proteolysis-targeting chimaeras (PROTACs) as well as molecular glues such as immunomodulatory drugs (IMiDs) and indisulam are drugs that induce interactions between substrate proteins and an E3 ubiquitin ligases for targeted protein degradation. Here, we develop a workflow based on proximity-dependent biotinylation by AirID to identify drug-induced neo-substrates of the E3 ligase cereblon (CRBN). Using AirID-CRBN, we detect IMiD-dependent biotinylation of CRBN neo-substrates in vitro and identify biotinylated peptides of well-known neo-substrates by mass spectrometry with high specificity and selectivity. Additional analyses reveal ZMYM2 and ZMYM2-FGFR1 fusion protein—responsible for the 8p11 syndrome involved in acute myeloid leukaemia—as CRBN neo-substrates. Furthermore, AirID-DCAF15 and AirID-CRBN biotinylate neo-substrates targeted by indisulam and PROTACs, respectively, suggesting that this approach has the potential to serve as a general strategy for characterizing drug-inducible protein–protein interactions in cells.

Suggested Citation

  • Satoshi Yamanaka & Yuto Horiuchi & Saya Matsuoka & Kohki Kido & Kohei Nishino & Mayaka Maeno & Norio Shibata & Hidetaka Kosako & Tatsuya Sawasaki, 2022. "A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27818-z
    DOI: 10.1038/s41467-021-27818-z
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    Cited by:

    1. Kohdai Yamada & Ryouhei Shioya & Kohei Nishino & Hirotake Furihata & Atsushi Hijikata & Mika K. Kaneko & Yukinari Kato & Tsuyoshi Shirai & Hidetaka Kosako & Tatsuya Sawasaki, 2023. "Proximity extracellular protein-protein interaction analysis of EGFR using AirID-conjugated fragment of antigen binding," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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