title: Importance of the polarity of the glycosaminoglycan chain on the interaction with FGF-1.
abstract: Heparin-like saccharides play an essential role in binding to the fibroblast growth factor (FGF)-1 and to their membrane receptors fibroblast growth factor receptor forming a ternary complex that is responsible of the internalization of the signal, via the dimerization of the intracellular regions of the receptor. In this study, we report the binding affinities between five synthetic hexasaccharides with human FGF-1 obtained by surface plasmon resonance experiments, and compare with the induced mitogenic activity previously obtained. These five oligosaccharides differ in sulfation pattern and in sequence. We have previously demonstrated that all the five hexasaccharides have similar 3D structure of the backbone. Consequently, the differences in binding affinity should have their origin in the substitution pattern. Subsequently, the different capacity for induction of mitogenic activity can be, at least partially, explained from these binding affinities. Interestingly, one of the oligosaccharides lacking axially symmetry ( 3: ) was biologically inactive, whereas the other ( 2: ) was the most active. The difference between both compounds is the order of the FGF-binding motifs along the chain relative to the carbohydrate polarity. We can conclude that the directionality of the GAG chain is essential for the binding and subsequent activation. The relative biological activity of the compounds with regular substitution pattern can be inferred from their values of IC50. Remarkably, the sulfate in position 6 of d-glucosamine was essential for the mitogenic activity but not for the interaction with FGF-1.
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Muñoz-García
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: M José
authors.initials: MJ
authors.lastname: García-Jiménez
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Carrero
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Canales
authors.affiliation: Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu 9, Madrid 28040, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.affiliation: CIC biomaGUNE, Biofunctional Nanomaterials Unit, San Sebastian 20009, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Martín-Lomas
authors.affiliation: CERMAV-CNRS, BP 53, Grenoble, cedex 9 38041, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: de Paz
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Angulo
authors.affiliation: Institute de Biologie Structural Jean Pierre Ebel, CNRS 41 rue Jules Horowitz, Grenoble Cedex 1 F-38027, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.affiliation: Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, 49, Sevilla 41092, Spain pedro.nieto@iiq.csic.es.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Nieto
mesh_terms: D016220:Fibroblast Growth Factor 1 / Q000737:chemistry*; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding; D020349:Surface Plasmon Resonance
chemical_list: D006025:Glycosaminoglycans; D016220:Fibroblast Growth Factor 1
keywords: FGF-1; SPR; glycosaminoglycan; heparin; protein–carbohydrate interaction