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J. Biol. Chem., Vol. 283, Issue 34, 23315-23325, August 22, 2008

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Crystal Structure of the Cold-active Aminopeptidase from Colwellia psychrerythraea, a Close Structural Homologue of the Human Bifunctional Leukotriene A₄ Hydrolase^*

Cédric Bauvois, Lilian Jacquamet, Adrienne L. Huston^¶, Franck Borel, Georges Feller^¶, and Jean-Luc Ferrer¹

From the Institut de Recherche Microbiologique J.-M. Wiame, Laboratoire de Microbiologie, Université Libre de Bruxelles, 1 rue E. Gryson, B-1070 Bruxelles, Belgium, Laboratoire de Cristallographie et Cristallogenèse des Protéines, Institut de Biologie Structurale J.-P. Ebel, CEA-CNRS-Université Joseph Fourier, 41 rue Jules Horowitz, F-38027 Grenoble cedex 1, France, and ^¶Laboratoire de Biochimie, Institut de Chimie B6a, Université de Liège, Sart-Tilman Campus, B-4000 Liège, Belgium

The crystal structure of a cold-active aminopeptidase (ColAP) from Colwellia psychrerythraea strain 34H has been determined, extending the number of crystal structures of the M1 metallopeptidase family to four among the 436 members currently identified. In agreement with their sequence similarity, the overall structure of ColAP displayed a high correspondence with leukotriene A4 hydrolase (LTA4H), a human bifunctional enzyme that converts leukotriene A4 (LTA4) in the potent chemoattractant leukotriene B4. Indeed, both enzymes are composed of three domains, an N-terminal saddle-like domain, a catalytic thermolysin-like domain, and a less conserved C-terminal -helical flat spiral domain. Together, these domains form a deep cavity harboring the zinc binding site formed by residues included in the conserved HEXXHX₁₈H motif. A detailed structural comparison of these enzymes revealed several plausible determinants of ColAP cold adaptation. The main differences involve specific amino acid substitutions, loop content and solvent exposure, complexity and distribution of ion pairs, and differential domain flexibilities. Such elements may act synergistically to allow conformational flexibility needed for an efficient catalysis in cold environments. Furthermore, the region of ColAP corresponding to the aminopeptidase active site of LTA4H is much more conserved than the suggested LTA4 substrate binding region. This observation supports the hypothesis that this region of the LTA4H active site has evolved in order to fit the lipidic substrate.

Received for publication, March 18, 2008 , and in revised form, May 28, 2008.

The atomic coordinates and structure factors (code 3CIA) 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 by the Commissariat à l'Energie Atomique (France), the Centre National pour la Recherche Scientifique (France), and grants from the Fonds National de la Recherche Scientifique, Belgium (to G. F.) and the National Science Foundation (to A. L. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed: Laboratoire de Cristallographie et Cristallogenèse des Protéines, Institut de Biologie Structurale J.-P. Ebel, CEA-CNRS-UJF, 41 rue Jules Horowitz, F-38027 Grenoble cedex 1, France. Tel.: 33-4-38-78-59-10; Fax: 33-4-38-78-51-22; E-mail: jean-luc.ferrer{at}ibs.fr.

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