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J. Biol. Chem., Vol. 277, Issue 41, 38764-38771, October 11, 2002

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Evidence for a Lectin Activity for Human Interleukin 3 and Modeling of Its Carbohydrate Recognition Domain^*

Jean-Pierre Zanetta^§, Roland Bindeus, Guy Normand^¶, Viviane Durier, Philippe Lagant, Emmanuel Maes, and Gérard Vergoten

From the  CNRS Unité Mixte de Recherche 8576, Glycobiologie Structurale et Fonctionnelle, Université des Sciences et Technologies de Lille Bâtiment C9, 59655 Villeneuve d'Ascq Cedex, France and the ^¶ Physiologie Cellulaire et Moléculaire de la Rétine, INSERM EPI9918, Hôpitaux Universitaire de Strasbourg, 1 place de l'Hôpital, 67091 Strasbourg Cedex, France

We demonstrate that human interleukin 3 (IL-3) is a lectin recognizing specifically the glycosaminoglycan part of a chondroitin sulfate proteoglycan (PGS3; Normand, G., Kuchler, S., Meyer, A., Vincendon, G., and Zanetta, J. P. (1988) J. Neurochem. 51, 665-676) isolated from the adult rat brain. The specificity of the interaction of this particular proteoglycan with IL-3 is due to the abundance of GlcA(2S)1,3GalNAc(4S)1 disaccharide units as suggested by ¹H NMR. Computational docking experiments of the lower energy conformers of the different disaccharides from chondroitin sulfates reveal a privileged binding site for GlcA(2S)1,3GalNAc(4S)1 (involving His-26, Arg-29, Asn-70, and Trp-104) localized in an area of IL-3 different from the receptor-binding domain previously identified by others (Bagley, C. J., Phillips, J., Cambareri, B., Vadas, M. A., and Lopez, A. F. (1996) J. Biol. Chem. 271, 31922-31928). Molecular modeling of the mutation P33G, described as increasing the biological activity of IL-3 without affecting its receptor binding (Lokker, N. A., Movva, N. R., Strittmatter, U., Fagg, B., and Zenke, G. (1991) J. Biol. Chem. 266, 10624-10631) provokes a change of the three-dimensional structure of IL-3, especially in the area of the putative carbohydrate recognition domain defined above. Computational docking experiments of the different disaccharides of chondroitin sulfates indicate a loss of affinity for the previous ligand but a higher affinity for the classic disaccharide of chondroitin-4-sulfate. This change from a rare and specific ligand to a more abundant constituent of proteoglycans could induce an increased quantitative association between the IL-3 receptors and its ligands and, consequently, an increased signaling.

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