9836
title and abstract
Rapamycin allosterically inhibits the proteasome.
Rapamycin is a canonical allosteric inhibitor of the mTOR kinase with immunosuppressive and pro-apoptotic activities. We found that in vitro rapamycin also regulates the proteasome, an essential intracellular protease of the ubiquitin-proteasome pathway. Rapamycin inhibits proteinase and selected peptidase activities of the catalytic core proteasome at low micromolar concentrations. Moreover, the drug interferes with binding of the 19S cap essential for processing of polyubiquitinylated substrates, and the PA200 activator to the 20S catalytic core proteasome. These protein complexes are known to bind to specific grooves on the α face region of the 20S core. A treatment with rapamycin affects conformational dynamics of the proteasomal gate, a centrally positioned within the α face and allosterically regulated element responsible for the intake of substrates. Interestingly, we showed that rapamycin shares all the proteasome targeting properties not only with other two-domain, closed-ring analogs (rapalogs), but also with its single domain mimics, and with seco-rapamycin. The latter is the first in vivo open-ring metabolite of rapamycin that does not affect mTOR. We hypothesize that the rapamycin and related compounds bind to the α face and allosterically impact the proteasome function. The implications of our finding for mechanism of in vivo actions of rapamycin and for design of novel allosteric drugs targeting the proteasome are discussed.