title: Evidence for a lectin activity for human interleukin 3 and modeling of its carbohydrate recognition domain.
abstract: 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)beta 1,3GalNAc(4S)beta 1 disaccharide units as suggested by (1)H NMR. Computational docking experiments of the lower energy conformers of the different disaccharides from chondroitin sulfates reveal a privileged binding site for GlcA(2S)beta 1,3GalNAc(4S)beta 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.
authors.affiliation: 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. Jean-Pierre.Zanetta@univ-lille1.fr
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Zanetta
authors.forename: Roland
authors.initials: R
authors.lastname: Bindeus
authors.forename: Guy
authors.initials: G
authors.lastname: Normand
authors.forename: Viviane
authors.initials: V
authors.lastname: Durier
authors.forename: Philippe
authors.initials: P
authors.lastname: Lagant
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Maes
authors.forename: Gérard
authors.initials: G
authors.lastname: Vergoten
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D007377:Interleukin-3; D037102:Lectins; D008024:Ligands