PA200 modulates immunoproteasome structure and activity
- Dušan Živković
- Amélie Bosc-Rosati
- Angelique Sanchez Dafun
- Fatme Mourtada
- Przemysław Grygier
- Ayse Seda Yazgili
- Marijke Jansma
- Michał Rawski
- Anna Czarna
- Stefan Bohn
- Krzysztof M. Zak
- André Santos Dias Mourão
- Norbert Reiling
- Linda Zemke
- Kai Guo
- Jürgen Behr
- Odile Burlet-Schiltz
- Grzegorz M. Popowicz
- Julien Marcoux
- Silke Meiners
- Marie-Pierre Bousquet
2026-08-11
The proteasome activator PA200 binds to the catalytic core of both standard proteasome (s20S) and the immunoproteasome (i20S); however, whether PA200 uses the same mechanisms to activate i20S remains unknown. In this work, the cryo-EM structures of singly- and doubly-capped i20S–PA200 complexes, combined with complementary in vitro biochemical assays, show 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 playing a potential role in regulating the i20S subunits’ expression. Overall, these findings suggest that PA200 contributes to the regulation of i20S function and dynamics.