The fibroblast growth factors (FGFs) form a large family of structurally related, multifunctional proteins that regulate various biological responses. They mediate cellular functions by binding to transmembrane FGF receptors, which are protein tyrosine kinases. FGF receptors are activated by oligomerization, and both this activation and FGF-stimulated biological responses require heparin-like molecules as well as FGF. 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 sugars, the nature of a biologically active complex has been unknown until now. Here we describe the X-ray crystal structure, at 2.9 A 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.
Fibroblast growth factors (FGFs) effect cellular responses by binding to FGF receptors (FGFRs). FGF bound to extracellular domains on the FGFR in the presence of heparin activates the cytoplasmic receptor tyrosine kinase through autophosphorylation. We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2. The crystal structure, determined by multiwavelength anomalous diffraction analysis of the selenomethionyl protein, is a dimeric assemblage of 1:1 ligand: receptor complexes. FGF is bound at the junction between the two domains of one FGFR, and two such units are associated through receptor:receptor and secondary ligand:receptor interfaces. Sulfate ion positions appear to mark the course of heparin binding between FGF molecules through a basic region on receptor D2 domains. This dimeric assemblage provides a structural mechanism for FGF signal transduction. Fibroblast growth factors (FGFs) stimulate a variety of cellular functions by binding to cell surface FGF receptors (FGFRs) in the presence of heparin proteoglycans. FGFRs are single-chain receptor tyrosine kinases that become activated through autophosphorylation that is thought to be induced through a mechanism of ligand-mediated receptor oligomerization (1). Receptor activation gives rise to a signal transduction cascade that leads to gene activation and diverse biological responses (2, 3). Both FGFs and FGFRs are expressed in defined spatial and temporal patterns, and they are involved in differentiation of both epithelial and neuronal cells. FGFs are potent mitogens for many cell types. Aberrant signaling through FGFR can lead to tumorigenesis and skeletal disorders (4).The FGF system has appreciable diversity in both ligands and receptors. The FGF family contains at least 15 distinct factors, highly conserved across mammalian species but divergent (30-70% sequence identity) among paralogs (2). The FGFR family includes four identified genes and numerous subtypes of alternatively spliced isoforms, particularly within the well characterized FGFR1 and FGFR2 types. Differential responses follow from this diversity.FGFRs have an extracellular portion imbued with the ligandbinding potential, a transmembrane segment, and a tyrosine kinase domain in the cytoplasm (2). The extracellular portion comprises three Ig-like domains, D1, D2, and D3, with an acidic stretch of approximately 30 residues, the acid box, between D1 and D2. Isoforms generated by alternate splicing events include receptors that lack Ig-like domain D1 or both D1 and the acid box, as well as variants having two alternative sequences for the C-terminal half of the third Ig-like domain. The FGF binding site has been mapped to domains D2, D3, and the interdomain linker.FGFs are secreted factors originally identified based on their mitogenicity toward fibroblasts. They are small proteins for which several FGF crystal structures have been determined; all have 12  strands in a -trefoil fold (2). Mutational analyses have mapped the sites of interaction...
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