STRUCTURE OF A HEPARIN-LINKED BIOLOGICALLY-ACTIVE DIMER OF FIBROBLASTGROWTH-FACTOR

The fibroblast growth factors (FGFs) form a large family of structural ly related, multifunctional proteins that regulate various biological responses(1.) They mediate cellular functions by binding to transmembr ane FGF receptors(2), which are protein tyrosine kinases. FGF receptor s are activated by oligomerization(3), and both this activation and FG F-stimulated biological responses require heparin-like molecules as we ll as FGF(4), Heparins are linear anionic polysaccharide chains; they are typically heterogeneously sulphated on alternating L-iduronic and D-glucosamino sugars, and are nearly ubiquitous in animal tissues as h eparan sulphate proteoglycans on cell surfaces and in the extracellula r matrix. Although several crystal structures have been described for FGF molecules in complexes with heparin-like sugars(5-7), the nature o f a biologically active complex has been unknown until now. Here we de scribe the X-ray crystal structure, at 2.9 Angstrom resolution, of a b iologically active dimer of human acidic FGF in a complex with a fully sulphated, homogeneous heparin decassacharide. The dimerization of he parin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and he terodimerization of the 12 known members of the FGF family.