The proteasome.

The proteasome is a large, 26S, multicatalytic protease that degrades polyubiquitinated proteins to small peptides. It is composed of two subcomplexes: a 20S core particle (CP) that carries the catalytic activity and a regulatory 19S regulatory particle (RP). The 20S CP is a barrel-shaped structure composed of four stacked rings, two identical outer α rings and two identical inner β rings. The eukaryotic α and β rings are composed each of seven distinct subunits, giving the 20S complex the general structure of α1–7β1–7β1–7α1–7. The catalytic sites are localized to some of the β subunits. Each extremity of the 20S barrel can be capped by a 19S RP, each composed of 17 distinct subunits: 9 in a “base” subcomplex, and 8 in a “lid” subcomplex. One important function of the 19S RP is to recognize ubiquitinated proteins and other potential substrates of the proteasome. Several ubiquitin-binding subunits of the 19S RP have been identified; however, their biological roles or modes of action have not been discerned. A second function of the 19S RP is to open an orifice in the α ring that will allow entry of the substrate into the proteolytic chamber. Also, since a folded protein would not be able to fit through the narrow proteasomal channel, it is assumed that the 19S particle unfolds substrates and inserts them into the 20S CP. Both the channel opening function and the unfolding of the substrate require metabolic energy, and, indeed, the 19S RP “base” contains six different ATPase subunits. Following degradation of the substrate, short peptides derived from the substrate are released, as well as reusable ubiquitin. a: Electron microscopy image of the 26S proteasome from the yeast S. cerevisiae. b: Schematic representation of the structure and function of the 26SA proteasome (with permission from Nature Publishing Group; published originally in Ciechanover et al.⁸³).