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Glycobiology Advance Access published online on April 28, 2004
Glycobiology, doi:10.1093/glycob/cwh088
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Received February 28, 2004
Revised April 15, 2004
Accepted April 16, 2004

ORIGINAL ARTICLES

Arg343 in human surfactant protein D governs discrimination between glucose and N-acetylglucosamine ligands

Martin J. Allen 1, Alain Laederach 2, Peter J. Reilly 3, Robert J. Mason 4, Dennis R. Voelker 5*

1 Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA
2 Department of Chemical Engineering, Iowa State University, Ames, IA 50011, USA; Bioinformatics and Computational Biology Program, Iowa State University, Ames, IA 50011, USA
3 Department of Chemical Engineering, Iowa State University, Ames, IA 50011, USA
4 Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA; Department of Medicine, University of Colorado, Health Sciences Center, Denver, CO 80262, USA
5 Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA; Department of Biochemistry and Molecular Genetics, University of Colorado, Health Sciences Center, Denver, CO 80262, USA

* To whom correspondence should be addressed. E-mail: voelkerd{at}njc.org.


  Abstract

Surfactant protein D (SP-D), one of the members of the collectin family of C-type lectins, is an important component of pulmonary innate immunity. SP-D binds carbohydrates in a calcium-dependent manner, but the mechanisms governing its ligand recognition specificity are not well understood. SP-D binds glucose (Glc) stronger than N-acetylglucosamine (GlcNAc). Structural superimposition of hSP-D with mannose binding protein C (MBP-C) complexed with GlcNAc reveals steric clashes between the ligand and the side chain of Arg343 in hSP-D. To test whether Arg343 contributes to Glc > GlcNAc recognition specificity, we constructed a computational model of Arg343->Val (R343V) mutant hSP-D based on homology with MBP-C. Automated docking of {alpha}-Me-Glc and {alpha}-Me-GlcNAc into wild-type hSP-D and the R343V mutant of hSP-D suggests that Arg343 is critical in determining ligand-binding specificity by sterically prohibiting one binding orientation. To empirically test the docking predictions, an R343V mutant recombinant hSP-D was constructed. Inhibition analysis shows that the R343V mutant binds both Glc and GlcNAc with higher affinity than the wild-type protein, and that the R343V mutant binds Glc and GlcNAc equally well. These data demonstrate that Arg343 is critical for hSP-D recognition specificity and plays a key role in defining ligand specificity differences between MBP and SP-D. Additionally, our results suggest that the number of binding orientations contributes to monosaccharide binding affinity.

Key words: C-type lectin, Glucose, Ligand binding, N-acetyl-D-glucosamine, Surfactant protein D


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