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J. Biol. Chem., Vol. 280, Issue 17, 17046-17056, April 29, 2005

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Ligand Specificity of Human Surfactant Protein D

EXPRESSION OF A MUTANT TRIMERIC COLLECTIN THAT SHOWS ENHANCED INTERACTIONS WITH INFLUENZA A VIRUS^*

Erika Crouch, Yizheng Tu, David Briner, Barbara McDonald, Kelly Smith, Uffe Holmskov¶, and Kevan Hartshorn||

From the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Institute for Medical Biology, University of Southern Denmark, Odense, Denmark, and the ^||Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118

Surfactant protein D is a pattern recognition molecule that plays diverse roles in immune regulation and anti-microbial host defense. Its interactions with known ligands are calcium-dependent and involve binding to the trimeric, C-type carbohydrate recognition domain. Surfactant protein D preferentially binds to glucose and related sugars. However, CL-43, a bovine serum lectin, which evolved through duplication of the surfactant protein D gene in ruminants, prefers mannose and mannose-rich polysaccharides. Surfactant protein D is characterized by two relatively conserved motifs at the binding face, along the edges of the shallow carbohydrate-binding groove. For CL-43, sequence alignments demonstrate a basic insertion, Arg-Ala-Lys (RAK), immediately N-terminal to the first motif. We hypothesized that this insertion contributes to the differences in saccharide selectivity and host defense function and compared the activities of recombinant trimeric neck + carbohydrate recognition domains of human surfactant protein D (NCRD) with CL-43 (RCL-43-NCRD) and selected NCRD mutants. Insertion of the CL-43 RAK sequence or a control Ala-Ala-Ala sequence (AAA) into the corresponding position in NCRD increased the efficiency of binding to mannan and changed the inhibitory potencies of competing saccharides to more closely resemble those of CL-43. In addition, RAK resembled CL-43 in its greater capacity to inhibit the infectivity of influenza A virus and to increase uptake of influenza by neutrophils.

Received for publication, December 10, 2004 , and in revised form, February 11, 2005.

^* This work was supported by National Institutes of Health Grants HL-44015 and HL-29594 (to E. C.) and HL-69031 (to K. H.). Portions of this work were also supported by Danish Medical Research Council Grant 9902278, the Novo-Nordic Foundation, and the Benson Foundation (to U. 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.

To whom correspondence should be addressed: Dept. of Pathology and Immunology, Campus Box 8118, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-454-8462; Fax: 314-454-5917; E-mail: crouch{at}path.wustl.edu.

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