Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors

Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic b...

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Veröffentlicht in:Science advances 2019-09, Vol.5 (9), p.eaaw3818-eaaw3818
Hauptverfasser: Felix, Jan, Weinhäupl, Katharina, Chipot, Christophe, Dehez, François, Hessel, Audrey, Gauto, Diego F, Morlot, Cecile, Abian, Olga, Gutsche, Irina, Velazquez-Campoy, Adrian, Schanda, Paul, Fraga, Hugo
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Sprache:eng
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Zusammenfassung:Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aaw3818