Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4

Fibroblast growth factors (FGFs) are heparin-binding polypeptides that affe ct the growth, differentiation, and migration of many cell types. FGFs sign al by binding and activating cell surface FGF receptors (FGFRs) with intrac ellular tyrosine kinase domains. The signaling involves ligand-induced rece ptor 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 for mation between the growth factor and receptor components. Whereas the hepar in/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 fra gment length, the minimal binding domains being contained within eight mono saccharide units. The FGFR4-binding saccharide domains contained both 2-O-s ulfated iduronic acid and 6-O-sulfated N-sulfoglucosamine residues, as show n by experiments with selectively desulfated heparin, compositional disacch aride analysis, and a novel exoenzyme-based sequence analysis of heparan su lfate oligosaccharides. Structurally distinct heparan sulfate octasaccharid es differed in binding to FGFR4. Sequence analysis suggested that the affin ity of the interaction depended on the number of 6-O-sulfate groups but not on their precise location.