title: Heparan sulfate-related oligosaccharides in ternary complex formation with fibroblast growth factors 1 and 2 and their receptors.
abstract: Biosynthesis of heparan sulfate (HS) is strictly regulated to yield products with cell/tissue-specific composition. Interactions between HS and a variety of proteins, including growth factors and morphogens, are essential for embryonic development and for homeostasis in the adult. Fibroblast growth factors (FGFs) and their various receptors (FRs) form ternary complexes with HS, as required for receptor signaling. Libraries of HS-related, radiolabeled oligosaccharides were generated by chemo-enzymatic modification of heparin and tested for affinity to immobilized FR ectodomains in the presence of FGF1 or FGF2. Experiments were designed to enable assessment of N-sulfated 8- and 10-mers with defined numbers of iduronic acid 2-O-sulfate and glucosamine 6-O-sulfate groups. FGF1 and FGF2 were found to require similar oligosaccharides in complex formation with FR1c-3c, FGF2 affording somewhat more efficient oligosaccharide recruitment than FGF1. FR4, contrary to FR1c-3c, bound oligosaccharides at physiological ionic conditions even in the absence of FGFs, and this interaction was further promoted by FGF1 but not by FGF2. In all systems studied, the stability of FGF-oligosaccharide-FR complexes correlated with the overall level of saccharide O-sulfation rather than on the precise distribution of sulfate groups.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Nadja
authors.initials: N
authors.lastname: Jastrebova
authors.forename: Maarten
authors.initials: M
authors.lastname: Vanwildemeersch
authors.forename: Alan C
authors.initials: AC
authors.lastname: Rapraeger
authors.forename: Guillermo
authors.initials: G
authors.lastname: Giménez-Gallego
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindahl
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002845:Chromatography; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry*; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D009844:Oligosaccharides / Q000737:chemistry*; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry; D013431:Sulfates / Q000737:chemistry
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D009844:Oligosaccharides; D017468:Receptors, Fibroblast Growth Factor; D013431:Sulfates