Oligomerization reduces heparin affinity but enhances receptor binding of fibroblast growth factor 2

The biological response of cells to fibroblast growth factors (FGFs) depend s on heparan sulphate glycosaminoglycans sharing particular structural moti fs. Heparin induced FGF dimerization has been suggested to mediate receptor dimerization and activation. Here we demonstrate that heparin-derived olig osaccharides that promote receptor binding and activation specifically indu ce the dimerization of basic FGF (FGF2), These heparin-induced dimers of FG F2 acquire high affinity for receptor binding and are biologically active. Using biotinylated FGF2 bound to immobilized streptavidin gradually saturat ed with biotin, enabled a quantitative analysis of heparin-dependent and he parin-independent FGF2 monomers and oligomers. Streptavidin induced FGF2 di mers bind and activate FGF receptors only in the presence of heparin. An ex cess of streptavidin, forcing biotin-FGF2 into monomers, reduces receptor b inding and blocks FGF-dependent cell proliferation. All these suggest predo minant receptor binding and activation by heparin associated FGF2 oligomers . Unexpectedly, heparin induced dimers and higher order oligomers lose most of their affinity towards heparin. Direct binding of soluble FGF receptors (FGFRs) to either monomers or dimers of FGF2, immobilized on heparin, conf irm the preferred association of FGFRs with dimers of FGF2. Computerized mo lecular docking predicts a cis-oriented FGF2 dimer, stabilized by heparin, which complies with all the experimental data.