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J. Biol. Chem., Vol. 282, Issue 49, 35814-35820, December 7, 2007

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Structural Basis for Innate Immune Sensing by M-ficolin and Its Control by a pH-dependent Conformational Switch^*

Virginie Garlatti, Lydie Martin, Evelyne Gout, Jean-Baptiste Reiser, Teizo Fujita^¶, Gérard J. Arlaud, Nicole M. Thielens, and Christine Gaboriaud¹

From the Laboratoire de Cristallographie et Cristallogénèse des Protéines and Laboratoire d'Enzymologie Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, Commissariat à l'Energie Atomique-CNRS-Université Joseph Fourier, 41 Rue Jules Horowitz, 38027 Grenoble, France and the ^¶Department of Biochemistry, Fukushima Medical University, Fukushima, Japan

Ficolins are soluble oligomeric proteins with lectin-like activity, assembled from collagen fibers prolonged by fibrinogen-like recognition domains. They act as innate immune sensors by recognizing conserved molecular markers exposed on microbial surfaces and thereby triggering effector mechanisms such as enhanced phagocytosis and inflammation. In humans, L- and H-ficolins have been characterized in plasma, whereas a third species, M-ficolin, is secreted by monocytes and macrophages. To decipher the molecular mechanisms underlying their recognition properties, we previously solved the structures of the recognition domains of L- and H-ficolins, in complex with various model ligands (Garlatti, V., Belloy, N., Martin, L., Lacroix, M., Matsushita, M., Endo, Y., Fujita, T., Fontecilla-Camps, J. C., Arlaud, G. J., Thielens, N. M., and Gaboriaud, C. (2007) EMBO J. 24, 623–633). We now report the ligand-bound crystal structures of the recognition domain of M-ficolin, determined at high resolution (1.75–1.8 Å), which provides the first structural insights into its binding properties. Interaction with acetylated carbohydrates differs from the one previously described for L-ficolin. This study also reveals the structural determinants for binding to sialylated compounds, a property restricted to human M-ficolin and its mouse counterpart, ficolin B. Finally, comparison between the ligand-bound structures obtained at neutral pH and nonbinding conformations observed at pH 5.6 reveals how the ligand binding site is dislocated at acidic pH. This means that the binding function of M-ficolin is subject to a pH-sensitive conformational switch. Considering that the homologous ficolin B is found in the lysosomes of activated macrophages (Runza, V. L., Hehlgans, T., Echtenacher, B., Zahringer, U., Schwaeble, W. J., and Mannel, D. N. (2006) J. Endotoxin Res. 12, 120–126), we propose that this switch could play a physiological role in such acidic compartments.

Received for publication, July 12, 2007 , and in revised form, September 21, 2007.

The atomic coordinates and structure factors (code 2jhm, 2jhk, 2jhi, 2jhl, and 2jhh) 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, the Centre National de la Recherche Scientifique, the Université Joseph Fourier, and Agence Nationale de la Recherche Grant ANR-05-MIIM-023-01. 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 To whom correspondence should be addressed. Tel.: 33-4-38789599; Fax: 33-4-38785122; E-mail: christine.gaboriaud{at}ibs.fr.

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