Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A

Accumulation of the CDK4/6 inhibitor p16INK4A in response to oncogenic transformation leads to cell cycle arrest and senescence and is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of oxidative stress and thus could potentially be regulated by the reversible oxidation of cysteines (redox signaling). Indeed, oxidation of the single cysteine in p16INK4A in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16INK4A is an all alpha-helical protein, but here we report that upon cysteine-dependent dimerization, p16INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-{beta} sheet structure, and typical dimensions found in electron microscopy. p16INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.