ABSTRACT

Many cellular processes, including stress response, cell cycle control and metabolic adaptation require protein turnover. The diversity of proteins that have to be degraded contrasts with the comparatively small number of proteases that are involved in this process.1 Due to their broad substrate specificity, the activity of these proteases has to be tigh tly contro lled . Therefore, they are either confined to organelles like the vacuole/lysosome,2 or they form sequestered compartments themselves, like the cage-like proteasome. The 26S proteasome is a large protein complex in eukaryotes that recognizes proteins marked for degradation by the attachment of a ub iqu itin chain3 and degrades them to oligopeptides.4 Electron microscopy revealed the modular architecture of 26S proteasomes. They consist of a proteolytic core component, the 20S proteasome that has regulatory components, the 19S caps, attached to it.5 The regulatory 19S caps, also referred to as PA700, are believed to be involved in ubiquitin recognition, ubiquitin editing, substrate unfolding and substrate translocation.6,7 They can be replaced by smaller, ATP-independent activators of proteolysis called PA28.8 Complexes of PA28 with 20S proteasomes have been analyzed by electron microscopy9 and the crystal structure of PA28a has recently been solved.10