{Reference Type}: Journal Article
{Title}: Amyloid formation and depolymerization of tumor suppressor p16INK4a are regulated by a thiol-dependent redox mechanism.
{Author}: Heath SG;Gray SG;Hamzah EM;O'Connor KM;Bozonet SM;Botha AD;de Cordovez P;Magon NJ;Naughton JD;Goldsmith DLW;Schwartfeger AJ;Sunde M;Buell AK;Morris VK;Göbl C;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jul 1
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-49581-7
{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.