ubiquitin receptor Rpn13 binds to Rpn2 and completes the base sub-complex. The lid covers one half of the AAA-ATPase hexamer (Rpt6/Rpt3/Rpt4) and, unexpectedly, directly contacts the 20S via Rpn6 and to lesser extent Rpn5. The subunits Rpn9, Rpn5, Rpn6, Rpn7, Rpn3, and Rpn12, which are structurally related among themselves and to subunits of the COP9 complex and eIF3 (hence called PCI subunits) assemble to a horseshoe-like structure enclosing the Rpn8/Rpn11 heterodimer. Rpn11, the deubiquitinating enzyme, is placed at the mouth of the AAA-ATPase hexamer, ideally positioned to remove ubiquitin moieties immediately before translocation of substrates into the 20S. The second ubiquitin receptor identified to date, Rpn10, is positioned at the periphery of the lid, near subunits Rpn8 and Rpn9. Conformational changes of 19S The 19S regulatory particle within the 26S proteasome holoenzyme has been observed in six strongly differing conformational states in the absence of substrates to date. A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of the AAA-domains. In the presence of ATP but absence of substrate three alternative, less abundant conformations of the 19S are adopted primarily differing in the positioning of the lid with respect to the AAA-ATPase module. In the presence of ATP-γS or a substrate, considerably more conformations have been observed displaying dramatic structural changes of the AAA-ATPase module. Some of the substrate-bound conformations bear high similarity to the substrate-free ones, but they are not entirely identical, particularly in the AAA-ATPase module. Prior to the 26S assembly, the 19S regulatory particle in a free form has also been observed in seven conformational states. Notably, all these conformers are somewhat different and present distinct features. Thus, the 19S regulatory particle can sample at least 20 conformational states under different physiological conditions. Regulation of the 20S by the 19S The 19S regulatory particle is responsible for stimulating the 20S to degrade proteins. A primary function of the 19S regulatory ATPases is to open the gate in the 20S that blocks the entry of substrates into the degradation chamber. The mechanism by which the proteasomal ATPase open this gate has been recently elucidated. 20S gate opening, and thus substrate degradation, requires the C-termini of the proteasomal ATPases, which contains a specific motif (i.e., HbYX motif). The ATPases C-termini bind into pockets in the top of the 20S, and tether the ATPase complex to the 20S proteolytic complex, thus joining