Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16^INK4A.

ABSTRACT: The tumor suppressor p16^INK4A induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16^INK4A is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that oxidation of the single cysteine in p16^INK4A in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16^INK4A is an all α-helical protein, but we find that upon cysteine-dependent dimerization, p16^INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. p16^INK4A amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16^INK4A through the formation of amyloid fibrils.

SUBMITTER: Gobl C 

PROVIDER: S-EPMC6812003 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature