PA200 modulates immunoproteasome structure and activity
Proteasomes help cells recycle proteins and shape immune responses. Here, the authors show that PA200 binds strongly to the immunoproteasome, reshaping its structure and activity to alter generation of immune-related pro
The proteasome activator PA200 binds to the catalytic core of both standard proteasome (s20S) and the immunoproteasome (i20S); however, the mechanisms of activation for i20S remain unknown. Cryo-EM structures of singly- and doubly-capped i20S–PA200 complexes, combined with in vitro biochemical assays, reveal that binding of the first PA200 induces allosteric bending of the i20S and widens the opposite α-ring, promoting higher PA200 occupancy and stronger activation compared to the s20S. PA200 also selectively modulates i20S proteolytic activity by enhancing peptide production and shifting cleavage specificity toward caspase-like activity. In cells and tissues co-expressing PA200, s20S, and i20S, PA200 preferentially associates with the i20S. Moreover, PA200 and i20S catalytic subunits are differentially regulated, with PA200 potentially regulating the i20S subunits’ expression. These findings suggest that PA200 contributes to the regulation of i20S function and dynamics.