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J. Biol. Chem., Vol. 276, Issue 20, 16868-16876, May 18, 2001

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Binding of Heparin/Heparan Sulfate to Fibroblast Growth Factor Receptor 4^*

Britt-Marie Loo^§, Johan Kreuger^§, Markku Jalkanen^¶, Ulf Lindahl^§, and Markku Salmivirta^§¶

From the  Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521 Turku, Finland, the ^§ Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123 Uppsala, Sweden, and ^¶ BioTie Therapies Corp., FIN-20520 Turku, Finland

Fibroblast growth factors (FGFs) are heparin-binding polypeptides that affect the growth, differentiation, and migration of many cell types. FGFs signal by binding and activating cell surface FGF receptors (FGFRs) with intracellular tyrosine kinase domains. The signaling involves ligand-induced receptor dimerization and autophosphorylation, followed by downstream transfer of the signal. The sulfated glycosaminoglycans heparin and heparan sulfate bind both FGFs and FGFRs and enhance FGF signaling by mediating complex formation between the growth factor and receptor components. Whereas the heparin/heparan sulfate structures involved in FGF binding have been studied in some detail, little information has been available on saccharide structures mediating binding to FGFRs. We have performed structural characterization of heparin/heparan sulfate oligosaccharides with affinity toward FGFR4. The binding of heparin oligosaccharides to FGFR4 increased with increasing fragment length, the minimal binding domains being contained within eight monosaccharide units. The FGFR4-binding saccharide domains contained both 2-O-sulfated iduronic acid and 6-O-sulfated N-sulfoglucosamine residues, as shown by experiments with selectively desulfated heparin, compositional disaccharide analysis, and a novel exoenzyme-based sequence analysis of heparan sulfate oligosaccharides. Structurally distinct heparan sulfate octasaccharides differed in binding to FGFR4. Sequence analysis suggested that the affinity of the interaction depended on the number of 6-O-sulfate groups but not on their precise location.

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