Structure of a heparin-linked biologically active dimer of fibroblast growth factor

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Abstract
The fibroblast growth factors (FGFs) form a large family of structurally related, multifunctional proteins that regulate various biological responses1. They mediate cellular functions by binding to transmembrane FGF receptors2, which are protein tyrosine kinases. FGF receptors are activated by oligomerization3, and both this activation and FGF-stimulated biological responses require heparin-like molecules as well as FGF4. 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 heparan sulphate proteoglycans on cell surfaces and in the extracellular matrix. Although several crystal structures have been described for FGF molecules in complexes with heparin-like sugars5,6,7, the nature of a biologically active complex has been unknown until now. Here we describe the X-ray crystal structure, at 2.9 Å resolution, of a biologically active dimer of human acidic FGF in a complex with a fully sulphated, homogeneous heparin decassacharide. The dimerization of heparin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and heterodimerization of the 12 known members of the FGF family.