A cysteine tweezer, oxidative switch, regulates proteasome disassembly

The accumulation of reactive oxygen species results in the modification of protein structures and promotes their misfolding and aggregation. This leads to activation of an integrated stress response. This response promotes chaperone gene expression and attenuation of protein synthesis, in an attempt to overcome the oxidative damage. Yet, misfolded proteins that have undergone irreversible oxidative modification must be removed from the intracellular environment. The primary intracellular protease responsible for the turnover of oxidatively damaged proteins is the 26S proteasome.

Based on our findings, we propose that an inherent cysteine “tweezer”, oxidative switch, within the 20S proteasome “senses” elevated oxidative condition, form a disulfide bond and promote stepwise proteasome disassembly, which may serve as a protective measure to remove damaged proteasome or perhaps underline a potential mechanism for damaged proteasomal subunits exchange. Using cryo-EM, cell biology and a novel family of in-house synthetized proteasome inhibitors targeting this oxidative switch, we captured intermediate structural states underlining these transitions within the 20S proteasome.