Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors
Felix, Jan ; Weinhäupl K. ; Chipot C. ; Dehez F. ; Hessel A. ; Gauto D.F. ; Morlot C. ; Abian, Olga (Universidad de Zaragoza) ; Gutsche I. ; Velazquez-Campoy A. (Universidad de Zaragoza) ; Schanda P. ; Fraga H.
Resumen: 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.
Idioma: Inglés
DOI: 10.1126/sciadv.aaw3818
Año: 2019
Publicado en: Science 5, 9 (2019), [18 pp.]
ISSN: 0036-8075
Factor impacto JCR: 41.845 (2019)
Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 2 / 70 = 0.029 (2019) - Q1 - T1
Factor impacto SCIMAGO: 13.11 - Multidisciplinary (Q1) - History and Philosophy of Science (Q1)
Financiación: info:eu-repo/grantAgreement/EUR/ERC-2012-StG-311318
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
Tipo y forma: Article (Published version)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes.
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Idioma: Inglés
DOI: 10.1126/sciadv.aaw3818
Año: 2019
Publicado en: Science 5, 9 (2019), [18 pp.]
ISSN: 0036-8075
Factor impacto JCR: 41.845 (2019)
Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 2 / 70 = 0.029 (2019) - Q1 - T1
Factor impacto SCIMAGO: 13.11 - Multidisciplinary (Q1) - History and Philosophy of Science (Q1)
Financiación: info:eu-repo/grantAgreement/EUR/ERC-2012-StG-311318
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
Tipo y forma: Article (Published version)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. Exportado de SIDERAL (2024-06-14-09:07:20)
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Record created 2019-12-12, last modified 2024-06-14