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J. Biol. Chem., Vol. 279, Issue 28, 29391-29397, July 9, 2004

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The X-ray Structure of Human Mannan-binding Lectin-associated Protein 19 (MAp19) and Its Interaction Site with Mannan-binding Lectin and L-ficolin^*

Lynn A. Gregory, Nicole M. Thielens¶, Misao Matsushita||, Rikke Sorensen**, Gérard J. Arlaud¶, Juan Carlos Fontecilla-Camps, and Christine Gaboriaud

From the Laboratoire de Cristallographie et Cristallogénèse des Protéines and the ^¶Laboratoire d'Enzymologie Moléculaire, Institut de Biologie Structurale, 38027 Grenoble Cedex 1, France, the ^||Department of Applied Biochemistry and Institute of Glycobiology, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan, and the ^**Department of Medical Microbiology and Immunology, University of Aarhus, DK 8000 Aarhus, Denmark

MAp19 is an alternative splicing product of the MASP-2 gene comprising the N-terminal CUB1-epidermal growth factor (EGF) segment of MASP-2, plus four additional residues at its C-terminal end. Like full-length MASP-2, it forms Ca²⁺-dependent complexes with mannan-binding lectin (MBL) and L-ficolin. The x-ray structure of human MAp19 was solved to a resolution of 2.5 Å. It shows a head to tail homodimer held together by interactions between the CUB1 module of one monomer and the EGF module of its counterpart. A Ca²⁺ ion bound to each EGF module stabilizes the dimer interfaces. A second Ca²⁺ ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu⁵², Asp⁶⁰, Asp¹⁰⁵, Ser¹⁰⁷, Asn¹⁰⁸, and a water molecule. Compared with its counterpart in human C1s, the N-terminal end of the MAp19 CUB1 module contains a 7-residue extension that forms additional inter-monomer contacts. To identify the residues involved in the interaction of MAp19 with MBL and L-ficolin, point mutants were generated and their binding ability was determined using surface plasmon resonance spectroscopy. Six mutations at Tyr⁵⁹, Asp⁶⁰, Glu⁸³, Asp¹⁰⁵, Tyr¹⁰⁶, and Glu¹⁰⁹ either strongly decreased or abolished interaction with both MBL and L-ficolin. These mutations map a common binding site for these proteins located at the distal end of each CUB1 module and stabilized by the Ca²⁺ ion.

Received for publication, March 9, 2004 , and in revised form, April 20, 2004.

^* This work was supported by the Commissariat à l'Energie Atomique, the Centre National de la Recherche Scientifique, and the Université Joseph Fourier, Grenoble. 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 atomic coordinates and structure factors (code 1SZB) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Both authors contributed equally to the work.

To whom correspondence should be addressed. Tel.: 33-4-38-78-95-99; Fax: 33-4-38-78-51-22; E-mail: christine.gaboriaud{at}ibs.fr.

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