PA200 modulates immunoproteasome structure and activity
Abstract
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.
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BibTeX
@article{zivkovic2026pa200,
title = {{PA200 modulates immunoproteasome structure and activity}},
author = {Dušan Živković and Amélie Bosc-Rosati and Angelique Sanchez Dafun and Fatme Mourtada and Przemysław Grygier and Ayse Seda Yazgili and Marijke Jansma and Michał Rawski and Anna Czarna and Stefan Bohn and Krzysztof M Zak and André Santos Dias Mourão and Norbert Reiling and Linda Zemke and Kai Guo and Jürgen Behr and Odile Burlet-Schiltz and Grzegorz M Popowicz and Julien Marcoux and Silke Meiners and Marie-Pierre Bousquet},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-75325-w},
url = {https://hal.science/hal-05746427v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PA200 modulates immunoproteasome structure and activity
AU - Dušan Živković
AU - Amélie Bosc-Rosati
AU - Angelique Sanchez Dafun
AU - Fatme Mourtada
AU - Przemysław Grygier
AU - Ayse Seda Yazgili
AU - Marijke Jansma
AU - Michał Rawski
AU - Anna Czarna
AU - Stefan Bohn
AU - Krzysztof M Zak
AU - André Santos Dias Mourão
AU - Norbert Reiling
AU - Linda Zemke
AU - Kai Guo
AU - Jürgen Behr
AU - Odile Burlet-Schiltz
AU - Grzegorz M Popowicz
AU - Julien Marcoux
AU - Silke Meiners
AU - Marie-Pierre Bousquet
PY - 2026
DA - 2026/09/11
JO - Nature Communications
DO - 10.1038/s41467-026-75325-w
UR - https://hal.science/hal-05746427v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -