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Amyloid formation and depolymerization of tumor suppressor p16INK4a are regulated by a thiol-dependent redox mechanism

Author

Listed:
  • Sarah G. Heath

    (University of Otago)

  • Shelby G. Gray

    (University of Canterbury)

  • Emilie M. Hamzah

    (University of Canterbury)

  • Karina M. O’Connor

    (University of Otago)

  • Stephanie M. Bozonet

    (University of Otago)

  • Alex D. Botha

    (University of Otago)

  • Pierre Cordovez

    (University of Otago)

  • Nicholas J. Magon

    (University of Otago)

  • Jennifer D. Naughton

    (University of Otago)

  • Dylan L. W. Goldsmith

    (University of Canterbury)

  • Abigail J. Schwartfeger

    (University of Canterbury)

  • Margaret Sunde

    (The University of Sydney)

  • Alexander K. Buell

    (Technical University of Denmark)

  • Vanessa K. Morris

    (University of Canterbury
    University of Canterbury)

  • Christoph Göbl

    (University of Otago
    University of Canterbury)

Abstract

The conversion of a soluble protein into polymeric amyloid structures is a process that is poorly understood. Here, we describe a fully redox-regulated amyloid system in which cysteine oxidation of the tumor suppressor protein p16INK4a leads to rapid amyloid formation. We identify a partially-structured disulfide-bonded dimeric intermediate species that subsequently assembles into fibrils. The stable amyloid structures disassemble when the disulfide bond is reduced. p16INK4a is frequently mutated in cancers and is considered highly vulnerable to single-point mutations. We find that multiple cancer-related mutations show increased amyloid formation propensity whereas mutations stabilizing the fold prevent transition into amyloid. The complex transition into amyloids and their structural stability is therefore strictly governed by redox reactions and a single regulatory disulfide bond.

Suggested Citation

  • Sarah G. Heath & Shelby G. Gray & Emilie M. Hamzah & Karina M. O’Connor & Stephanie M. Bozonet & Alex D. Botha & Pierre Cordovez & Nicholas J. Magon & Jennifer D. Naughton & Dylan L. W. Goldsmith & Ab, 2024. "Amyloid formation and depolymerization of tumor suppressor p16INK4a are regulated by a thiol-dependent redox mechanism," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49581-7
    DOI: 10.1038/s41467-024-49581-7
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    References listed on IDEAS

    as
    1. Paolo Arosio & Thomas C. T. Michaels & Sara Linse & Cecilia Månsson & Cecilia Emanuelsson & Jenny Presto & Jan Johansson & Michele Vendruscolo & Christopher M. Dobson & Tuomas P. J. Knowles, 2016. "Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
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