Design principles that protect the proteasome from self-destruction.

The proteasome is a powerful intracellular protease that can degrade effectively any protein, self or foreign, for regulation, quality control, or immune response. Proteins are targeted for degradation by localizing them to the proteasome, typically by ubiquitin tags. At the same time, the proteasome is built from ~33 subunits, and their assembly into the complex and activity are tuned by post-translational modifications on long disordered regions on the subunits. Molecular modeling and biochemical experiments show that some of the disordered regions of proteasomal subunits can access the substrate recognition sites. All disordered regions tested, independent of location, are constructed from amino acid sequences that escape recognition. Replacing a disordered region with a sequence that is recognized by the proteasome leads to self-degradation and, in the case of an essential subunit, cell death.