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 de Cordovez, Nicholas J. Magon, Jennifer D. Naughton, Dylan L.W. Goldsmith, Abigail J. Schwartfeger, Margaret Sunde, Alexander K. Buell, Vanessa K. Morris*, Christoph Göbl*

*Corresponding author for this work

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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.
Original languageEnglish
Article number5535
JournalNature Communications
Volume15
Number of pages16
ISSN2041-1723
DOIs
Publication statusPublished - 2024

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