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

J. Felix, K. Weinhäupl, C. Chipot, F. Dehez, A. Hessel, D.F. Gauto, C. Morlot, O. Abian, I. Gutsche, A. Velazquez-Campoy, P. Schanda, H. Fraga, Science Advances 5 (2019).


Journal Article | Published | English
Author
Felix, Jan; Weinhäupl, Katharina; Chipot, Christophe; Dehez, François; Hessel, Audrey; Gauto, Diego F.; Morlot, Cecile; Abian, Olga; Gutsche, Irina; Velazquez-Campoy, Adrian; Schanda, PaulIST Austria ; Fraga, Hugo
All
Abstract
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.
Publishing Year
Date Published
2019-09-04
Journal Title
Science Advances
Volume
5
Issue
9
Article Number
eaaw3818
ISSN
IST-REx-ID

Cite this

Felix J, Weinhäupl K, Chipot C, et al. Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Science Advances. 2019;5(9). doi:10.1126/sciadv.aaw3818
Felix, J., Weinhäupl, K., Chipot, C., Dehez, F., Hessel, A., Gauto, D. F., … Fraga, H. (2019). Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Science Advances, 5(9). https://doi.org/10.1126/sciadv.aaw3818
Felix, Jan, Katharina Weinhäupl, Christophe Chipot, François Dehez, Audrey Hessel, Diego F. Gauto, Cecile Morlot, et al. “Mechanism of the Allosteric Activation of the ClpP Protease Machinery by Substrates and Active-Site Inhibitors.” Science Advances 5, no. 9 (2019). https://doi.org/10.1126/sciadv.aaw3818.
J. Felix et al., “Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors,” Science Advances, vol. 5, no. 9, 2019.
Felix J, Weinhäupl K, Chipot C, Dehez F, Hessel A, Gauto DF, Morlot C, Abian O, Gutsche I, Velazquez-Campoy A, Schanda P, Fraga H. 2019. Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Science Advances. 5(9).
Felix, Jan, et al. “Mechanism of the Allosteric Activation of the ClpP Protease Machinery by Substrates and Active-Site Inhibitors.” Science Advances, vol. 5, no. 9, eaaw3818, American Association for the Advancement of Science, 2019, doi:10.1126/sciadv.aaw3818.
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