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J. Biol. Chem., Vol. 283, Issue 5, 2871-2882, February 1, 2008

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A New Autocatalytic Activation Mechanism for Cysteine Proteases Revealed by Prevotella intermedia Interpain A^*

Noemí Mallorquí-Fernández¹, Surya P. Manandhar¹, Goretti Mallorquí-Fernández, Isabel Usón^¶, Katarzyna Wawrzonek^||, Tomasz Kantyka^||, Maria Solà², Ida B. Thøgersen^**, Jan J. Enghild^**, Jan Potempa^||3, and F. Xavier Gomis-Rüth⁴

From the Departament de Biologia Estructural and the ^¶Institució Catalana de Recerca i Estudis Avançats, Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, c/Jordi Girona, 18-26, Barcelona 08034, Spain, the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, the ^||Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland, and the ^**Department of Molecular Biology, Science Park, University of Århus, Gustav Wieds Vej 10C, 8000 Århus C, Denmark

Prevotella intermedia is a major periodontopathogen contributing to human gingivitis and periodontitis. Such pathogens release proteases as virulence factors that cause deterrence of host defenses and tissue destruction. A new cysteine protease from the cysteine-histidine-dyad class, interpain A, was studied in its zymogenic and self-processed mature forms. The latter consists of a bivalved moiety made up by two subdomains. In the structure of a catalytic cysteine-to-alanine zymogen variant, the right subdomain interacts with an unusual prodomain, thus contributing to latency. Unlike the catalytic cysteine residue, already in its competent conformation in the zymogen, the catalytic histidine is swung out from its active conformation and trapped in a cage shaped by a backing helix, a zymogenic hairpin, and a latency flap in the zymogen. Dramatic rearrangement of up to 20Å of these elements triggered by a tryptophan switch occurs during activation and accounts for a new activation mechanism for proteolytic enzymes. These findings can be extrapolated to related potentially pathogenic cysteine proteases such as Streprococcus pyogenes SpeB and Porphyromonas gingivalis periodontain.

Received for publication, October 11, 2007 , and in revised form, November 7, 2007.

The atomic coordinates and structure factors (code 3bb7 and 3bba) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the former Spanish Ministry for Science and Technology (Grants BIO2004-20369-E and BIO2003-06653); the Spanish Ministry for Education and Science (Grants BIO2006-02668, BIO2006-14139, and BFU2006-09593, and CONSOLIDER-INGENIO 2010 Project "La Factoría de Cristalización" CSD2006-00015); European Union (EU) FP6 Integrated Project LSHC-CT-2003-503297 "CANCERDEGRADOME"; EU FP6 Strep Project 18830 "CAMP"; the "AVON-Project" (Grant 2005X0648) from the Spanish Association Against Cancer; the Danish National Science Research Council (to J. J. E.); and by Ministry for Science and Higher Education (Warsaw, Poland) and National Institutes of Health Grant DE 09761 (to J. P.). Funding for synchrotron diffraction data collection was provided by the European Synchrotron Radiation Facility and the EU. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Beneficiary of the "Ramón y Cajal" Program of the Spanish Ministry for Science and Education.

³ To whom correspondence may be addressed. Tel.: 44-151-664-6343; Fax: 44-151-706-5809; E-mail: potempa{at}mol.uj.edu.pl.

⁴ To whom correspondence may be addressed. Tel.: 34-934-006-144; Fax: 34-932-045-904; E-mail: xgrcri{at}ibmb.csic.es.

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