Figure 2.

Structure and translocation mechanism of the human 26S proteasome. (a) Cryo-EM structure of the substrate-bound human proteasome in state E_B at 3.3 Å (EMDB ID: 9218; PDB ID: 6MSE). The RPT1 density is omitted to show the substrate density inside the ATPase ring. The RPN13 density is not observed in this structure. (b) A close-up view of the quaternary interface around the isopeptide bond between substrate and ubiquitin. (c) Architecture of pore loop staircase interacting with the substrate. Aromatic residues in pore-1 loops are labelled. (d) Molecular model of RPT5 in state E_B, with ATP bound and substrate engaged. (e) Schematic of mechanical substrate translocation of proteasomal ATPases. Synchronization of nucleotide processing in three adjacent ATPases (left) causes differential vertical rigid-body rotations in each substrate-engaged ATPase that cooperatively transfer the substrate (right).