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J. Biol. Chem., Vol. 281, Issue 26, 18008-18014, June 30, 2006

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Contributions of Phenylalanine 335 to Ligand Recognition by Human Surfactant Protein D

RING INTERACTIONS WITH SP-D LIGANDS^*

Erika Crouch¹, Barbara McDonald, Kelly Smith, Tanya Cafarella, Barbara Seaton, and James Head

From the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110 and Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118

Surfactant protein D (SP-D) is an innate immune effector that contributes to antimicrobial host defense and immune regulation. Interactions of SP-D with microorganisms and organic antigens involve binding of glycoconjugates to the C-type lectin carbohydrate recognition domain (CRD). A trimeric fusion protein encoding the human neck+CRD bound to the aromatic glycoside p-nitrophenyl--D-maltoside with nearly a log-fold higher affinity than maltose, the prototypical competitor. Maltotriose, which has the same linkage pattern as the maltoside, bound with intermediate affinity. Site-directed substitution of leucine for phenylalanine 335 (Phe-335) decreased affinities for the maltoside and maltotriose without significantly altering the affinity for maltose or glucose, and substitution of tyrosine or tryptophan for leucine restored preferential binding to maltotriose and the maltoside. A mutant with alanine at this position failed to bind to mannan or maltose-substituted solid supports. Crystallographic analysis of the human neck+CRD complexed with maltotriose or p-nitrophenyl-maltoside showed stacking of the terminal glucose or nitrophenyl ring with the aromatic ring of Phe-335. Our studies indicate that Phe-335, which is evolutionarily conserved in all known SP-Ds, plays important, if not critical, roles in SP-D function.

Received for publication, February 23, 2006 , and in revised form, April 21, 2006.

^* This work was supported by National Institutes of Health Grants HL-44015 and HL-29594 (to E. C. C.). 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 2GGU and 2GGX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed: Dept. of Pathology and Immunology, Campus Box 8118, Washington University School of Medicine, 660 S. 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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