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)