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Originally published In Press as doi:10.1074/jbc.M101027200 on March 6, 2001

J. Biol. Chem., Vol. 276, Issue 20, 17052-17057, May 18, 2001
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The Mannose/N-Acetylgalactosamine-4-SO4 Receptor Displays Greater Specificity for Multivalent than Monovalent Ligands*

Daniel S. Roseman and Jacques U. BaenzigerDagger

From the Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Recognition of carbohydrates on glycosylated molecules typically requires multivalent interactions with receptors. Monovalent forms of terminal saccharides engaged by the receptor binding sites typically display weak affinities in the mM range and poor specificity. In contrast, multivalent forms of the same saccharides are bound with strong affinity (10-7-10-9 M) and significantly greater specificity. Although multivalency can readily account for increased affinity, the molecular basis for enhanced specificity is not well understood. We have examined the specificity of the cysteine-rich domain of the mannose/GalNAc-4-SO4 receptor using monovalent and multivalent forms of the trisaccharide GalNAcbeta 1,4GlcNAcbeta 1,2Manalpha (GGnM) sulfated at either the C4 (S4GGnM) or C3 (S3GGnM) hydroxyl of the terminal GalNAc. Monovalent S4GGnM and S3GGnM have Ki values of 25.8 and 16.2 µM, respectively. Multivalent conjugates of the same GalNAc-4-SO4- and GalNAc-3-SO4-bearing trisaccharides (6.7 mol of trisaccharide/mol of bovine serum albumin) have Ki values of 0.013 and 0.170 µM, respectively. The 2000-fold versus 95-fold change in affinity seen for the multivalent forms of these 4-sulfated and 3-sulfated trisaccharides reflects a difference in the impact of conformational entropy. A large fraction of the SO4-3-GalNAc structures exists in a form that is not favorable for binding to the Cys-rich domain. This reduces the effective concentration of SO4-3-GalNAc as compared with SO4-4-GalNAc under the same conditions and results in a markedly lower association rate. This difference in association rate accounts for the 12-fold difference in the rate of clearance from the blood seen with S4GGnM-BSA and S3GGnM-BSA in vivo.

* This work was supported by National Institutes of Health Grants R37-CA21923 and R01-DK41738.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 314-362-8730; Fax: 314-362-8888; E-mail: Baenziger@Pathology.WUSTL.EDU.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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