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

Author:

Heath Sarah G.ORCID,Gray Shelby G.ORCID,Hamzah Emilie M.,O’Connor Karina M.,Bozonet Stephanie M.ORCID,Botha Alex D.ORCID,de Cordovez Pierre,Magon Nicholas J.,Naughton Jennifer D.,Goldsmith Dylan L. W.,Schwartfeger Abigail J.ORCID,Sunde MargaretORCID,Buell Alexander K.ORCID,Morris Vanessa K.ORCID,Göbl ChristophORCID

Abstract

AbstractThe 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.

Funder

Manatu Hauora | Health Research Council of New Zealand

Canterbury Medical Research Foundation

Royal Society of New Zealand Marsden Fund, # 21-UOO-128

Publisher

Springer Science and Business Media LLC

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