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J. Biol. Chem., Vol. 280, Issue 6, 4307-4312, February 11, 2005

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Glycan Array Screening Reveals a Candidate Ligand for Siglec-8^*

Bruce S. Bochner, Richard A. Alvarez¶, Padmaja Mehta||, Nicolai V. Bovin**, Ola Blixt, John R. White, and Ronald L. Schnaar¶¶

From the Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, ^¶Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, ^||Cardiovascular Biology Research Program, The Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, ^**Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia, Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, and ^¶¶Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is selectively expressed on human eosinophils, basophils, and mast cells, where it regulates their function and survival. Previous studies demonstrated sialic acid-dependent binding of Siglec-8 but failed to reveal significant substructure specificity or high affinity of that binding. To test a broader range of potential ligands, a Siglec-8-Ig chimeric protein was tested for binding to 172 different glycan structures immobilized as biotinylated glycosides on a 384-well streptavidin-coated plate. Of these, 40 structures were sialylated. Among these, avid binding was detected to a single defined glycan, NeuAc2–3(6-O-sulfo)Gal1–4[Fuc1–3]GlcNAc, also referred to in the literature as 6'-sulfo-sLe^x. Notably, neither unsulfated sLe^x (NeuAc2–3Gal1–4[Fuc1–3]GlcNAc) nor an isomer with the sulfate on the 6-position of the GlcNAc residue (6-sulfo-sLe^x, NeuAc2–3Gal1–4[Fuc1–3](6-O-sulfo)GlcNAc) supported detectable binding. Subsequent secondary screening was performed using surface plasmon resonance. Biotin glycosides immobilized on streptavidin biosensor chips were exposed to Siglec-8-Ig in solution. Whereas surfaces derivatized with sLe^x and 6-sulfo-sLe^x failed to support detectable Siglec-8 binding, 6'-sulfo-sLe^x supported significant binding with a K_d of 2.3 µM.In a separate test of binding specificity, aminopropyl glycosides were covalently immobilized at different concentrations on activated (N-hydroxysuccinimidyl) glass surfaces (Schott-Nexterion Slide H). Subsequent exposure to Siglec-8-Ig precomplexed with fluorescein isothiocyanate anti-human Fc resulted in fluorescent signals at immobilized concentrations of 6'-sulfo-sLe^x of <5 pmol/spot. In contrast, sLe^x and 6-sulfo-sLe^x did not support any Siglec-8 binding at the highest concentration tested (300 pmol/spot). We conclude that Siglec-8 binds preferentially to the sLe^x structure bearing an additional sulfate ester on the galactose 6-hydroxyl.

Received for publication, November 2, 2004 , and in revised form, November 23, 2004.

Note Added in Proof—Using a similar glycan array approach, it is now known that 6'-sulfo-sLe^x is also a ligand for langerin (Galustian, C., Park, G. G., Chai, W., Kiso, M., Bruening, S. A., Kang, Y. S., Steinman, R. M., and Feizi, T. (2004) Int. Immunol. 16, 853–866).

^* This work was supported in part by the Consortium for Functional Glycomics under NIGMS, National Institutes of Health Grant GM62116. It was also supported by National Institutes of Health Grant AI41472 (to B. S. B.) and the Russian Academy of Sciences Physicochemical Biology Program (to N. V. B.). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

To whom correspondence should be addressed: Division of Allergy & Clinical Immunology, Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Rm. 2B.71, Baltimore, MD 21224-6821. Tel.: 410-550-2101; Fax: 410-550-1733; E-mail: bbochner{at}jhmi.edu.

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