Publikation: Evidence for the existence of a non-catalytic modifier site of peptide hydrolysis by the 20 S proteasome
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The 20 S proteasome is an endoprotease complex that preferentially cleaves peptides C-terminal of hydrophobic, basic, and acidic residues. Recently, we showed that these specific activities, classified as chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide-hydrolyzing (PGPH) activity, are differently affected by Ritonavir, an inhibitor of human immunodeficiency virus-1 protease. Ritonavir competitively inhibited the chymotrypsin-like activity, whereas the trypsin-like activity was enhanced. Here we demonstrate that the Ritonavir-mediated up-regulation of the trypsin-like activity is not affected by specific active site inhibitors of the chymo-trypsin-like and PGPH activity. Moreover, we show that the mutual regulation of chymotrypsin-like and PGPH activities by their substrates as described previously by a "cyclical bite-chew" model is not affected by selective inhibitors of the respective active sites. These data challenge the bite-chew model and suggest that effectors of proteasome activity can act by binding to non-catalytic sites. Accordingly, we propose a kinetic "two-site modifier" model that assumes that the substrate (or effector) may bind to an active site as well as to a second non-catalytic modifier site. This model appears to be valid as it describes the complex kinetic effects of Ritonavir very well. Since Ritonavir partially inhibits major histocompatibility complex class I restricted antigen presentation, the postulated modifier site may be required to coordinate the active centers of the proteasome for the production of class I peptide ligands.
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SCHMIDTKE, Gunter, Sabine EMCH, Marcus GRÖTTRUP, Hermann-Georg HOLZHÜTTER, 2000. Evidence for the existence of a non-catalytic modifier site of peptide hydrolysis by the 20 S proteasome. In: Journal of Biological Chemistry. 2000, 275(29), pp. 22056-22063. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.M002513200BibTex
@article{Schmidtke2000-07-21Evide-22167, year={2000}, doi={10.1074/jbc.M002513200}, title={Evidence for the existence of a non-catalytic modifier site of peptide hydrolysis by the 20 S proteasome}, number={29}, volume={275}, issn={0021-9258}, journal={Journal of Biological Chemistry}, pages={22056--22063}, author={Schmidtke, Gunter and Emch, Sabine and Gröttrup, Marcus and Holzhütter, Hermann-Georg} }
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