The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress or aging can induce the build-up of IDPs result-ing in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neuro-degenerative diseases. Drugs that facilitate 20S-mediated proteolysis have therefore many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small mole-cule TCH-165, resulting in an increase in 20S levels. The increase of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome com-plexes (19S-20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.
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