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Cadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs

Author

Listed:
  • Linda Lauinger

    (University of California, Irvine)

  • Anna Andronicos

    (University of California, Irvine)

  • Karin Flick

    (University of California, Irvine)

  • Clinton Yu

    (University of California, Irvine)

  • Geetha Durairaj

    (University of California, Irvine)

  • Lan Huang

    (University of California, Irvine)

  • Peter Kaiser

    (University of California, Irvine)

Abstract

The F-box domain is a highly conserved structural motif that defines the largest class of ubiquitin ligases, Skp1/Cullin1/F-box protein (SCF) complexes. The only known function of the F-box motif is to form the protein interaction surface with Skp1. Here we show that the F-box domain can function as an environmental sensor. We demonstrate that the F-box domain of Met30 is a cadmium sensor that blocks the activity of the SCFMet30 ubiquitin ligase during cadmium stress. Several highly conserved cysteine residues within the Met30 F-box contribute to binding of cadmium with a KD of 8 µM. Binding induces a conformational change that allows for Met30 autoubiquitylation, which in turn leads to recruitment of the segregase Cdc48/p97/VCP followed by active SCFMet30 disassembly. The resulting inactivation of SCFMet30 protects cells from cadmium stress. Our results show that F-box domains participate in regulation of SCF ligases beyond formation of the Skp1 binding interface.

Suggested Citation

  • Linda Lauinger & Anna Andronicos & Karin Flick & Clinton Yu & Geetha Durairaj & Lan Huang & Peter Kaiser, 2024. "Cadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48184-6
    DOI: 10.1038/s41467-024-48184-6
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    References listed on IDEAS

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    1. Debasish Paul & Stephen C. Kales & James A. Cornwell & Marwa M. Afifi & Ganesha Rai & Alexey Zakharov & Anton Simeonov & Steven D. Cappell, 2022. "Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Stefan Kepinski & Ottoline Leyser, 2005. "The Arabidopsis F-box protein TIR1 is an auxin receptor," Nature, Nature, vol. 435(7041), pages 446-451, May.
    3. Nihal Dharmasiri & Sunethra Dharmasiri & Mark Estelle, 2005. "The F-box protein TIR1 is an auxin receptor," Nature, Nature, vol. 435(7041), pages 441-445, May.
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