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

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, Abigail J. Schwartfeger, Margaret Sunde, Alexander K. Buell, Vanessa K. Morris () and Christoph Göbl ()
Additional contact information
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
Christoph Göbl: University of Otago

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49581-7

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