Importance of the Polarity of the Glycosaminoglycan Chain on the Interaction with Fgf-1

Muñoz-García, Juan C., Garcia-Jimenez, Maria Jose, Carrero, Paula, Canales, Angeles, Jimenez-Barbero, Jesus, Martin-Lomas, Manuel, Imberty, Anne, De Paz, José-luis, Angulo, Jesus, Lortat-Jacob, Hugues and Nieto, Pedro M. (2014) Importance of the Polarity of the Glycosaminoglycan Chain on the Interaction with Fgf-1. Glycobiology, 24 (11). pp. 1004-1009. ISSN 0959-6658

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Abstract

Heparin-like saccharides play an essential role in binding to the FGF-1 and to their membrane receptors FGFR 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 Resonance Plasmon (SPR) experiments, and compare with the induced mitogenic activity previously obtained. These five oligosaccharides differ in the sulphation pattern and in the 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 of 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 sulphate in position 6 of D-Glucosamine was essential for the mitogenic activity but not for the interaction with FGF-1.

Item Type: Article
Uncontrolled Keywords: heparin,glycosaminoglycans,fgf-1,protein-carbohydrate interactions,surface plasmon resonance
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 25 Jul 2014 15:24
Last Modified: 17 Mar 2020 20:03
URI: https://ueaeprints.uea.ac.uk/id/eprint/49719
DOI: 10.1093/glycob/cwu071

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