Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin

@article{Pellegrini2000CrystalSO,
  title={Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin},
  author={Luca Pellegrini and D. Burke and Frank von Delft and Barbara Mulloy and Tom L. Blundell},
  journal={Nature},
  year={2000},
  volume={407},
  pages={1029-1034}
}
Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) and heparan sulphate proteoglycan in a specific complex on the cell surface. Direct involvement of the heparan sulphate glycosaminoglycan polysaccharide in the molecular association between FGF and its receptor is essential for biological activity. Although… 
ACTIVATION MECHANISM OF FIBROBLAST GROWTH FACTOR RECEPTOR TYROSINE KINASE REVEALED BY CRYSTAL STRUCTURE OF FIBROBLAST GROWTH FACTOR RECEPTOR ECTODOMAIN BOUND TO FIBROBLAST GROWTH FACTOR AND HEPARIN.
TLDR
The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling and suggests possible mechanisms for receptor activation, based on a heparin-induced conformational change in the receptor, and for higher order FGFR clustering.
Structural specificity of heparin binding in the fibroblast growth factor family of proteins
TLDR
It is shown that in addition to the ionic interactions, optimal van der Waals contact between the HSGAG oligosaccharide and the protein is also very important in influencing the specificity of FGF–HSGAG interactions.
Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces.
TLDR
Fibroblast growth factors FGF9, originally discovered as a glia-activating factor, shares 30% sequence identity with other FGFs and has a unique spectrum of target-cell specificity.
Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling*
TLDR
The findings presented here provide direct evidence of FGF2 dimerization in mediating F GF2 signaling using a combination of biochemical, biophysical, and site-directed mutagenesis approaches.
Binding of Heparin/Heparan Sulfate to Fibroblast Growth Factor Receptor 4*
TLDR
Structural characterization of heparin/heparan sulfate oligosaccharides with affinity toward FGFR4 is performed and it is suggested that the affinity of the interaction depended on the number of 6-O-sulfate groups but not on their precise location.
Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligomers of heparin.
TLDR
It is demonstrated that, in the FGF (fibroblast growth factor)-FGFR (FGF receptor) system, multimers of the minimal complex composed of two FGF1 and two FGFR2 protomers can form on a single chain of the co-receptor heparin.
Evidence that the intracellular domain of FGF receptor 2IIIb affects contact of the ectodomain with two FGF7 ligands.
TLDR
It is proposed that the differences in crosslinking report differences in relationships among subunits in the ectodomain of the complex that are affected by the amino terminus of FGF and the FGFR intracellular domain.
Identification of Receptor and Heparin Binding Sites in Fibroblast Growth Factor 4 by Structure-Based Mutagenesis
TLDR
FGF4, like FGF2, but unlike FGF1, engages the βC′-βE loop in D3 and thus can differentiate between the IIIc and IIIb splice isoforms of FGFRs for binding, and it is shown that FGF4 needs to interact with both the 2-O and 6-O-sulfates in heparin to exert its optimal biological activity.
...
...

References

SHOWING 1-10 OF 31 REFERENCES
Structure of a heparin-linked biologically active dimer of fibroblast growth factor
TLDR
The dimerization of heparin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and heterodimerizing of the 12 known members of the FGF family.
Structural interactions of fibroblast growth factor receptor with its ligands.
TLDR
The crystal structure, determined by multiwavelength anomalous diffraction analysis of the selenomethionyl protein, is a dimeric assemblage of 1:1 ligand:receptor complexes that provides a structural mechanism for FGF signal transduction.
An essential heparin-binding domain in the fibroblast growth factor receptor kinase.
TLDR
The results indicate that the FGF receptor is a ternary complex of heparan sulfate proteoglycan, tyrosine kinase transmembrane glycoprotein, and ligand.
Energetic characterization of the basic fibroblast growth factor-heparin interaction: identification of the heparin binding domain.
TLDR
The combination of site-directed mutagenesis and titrating calorimetry permitted an analysis of the energetic contributions of individual bF GF residues in the binding of heparin to bFGF, indicating that pure electrostatic interactions contribute only 30% of the binding free energy as analyzed by polyelectrolyte theory and that more specific nonionic interactions, such as hydrogen bonding and van der Waals packing, contribute the majority of the free energy for this binding reaction.
Ligand-specific Structural Domains in the Fibroblast Growth Factor Receptor (*)
TLDR
It is suggested that alternately spliced exon IIIc plays no active role in binding of the three ligands, and extension of the fragment by five additional highly conserved residues (SD(P/A)QP) within a distinct constitutive structural domain (fl1) in Loop III restricts the binding of FGF-7 without effect on FGFs 1 and 2.
Heparin Structure and Interactions with Basic Fibroblast Growth Factor
TLDR
No significant conformational change in bFGF occurred upon heparin oligosaccharide binding, which suggests that heparIn primarily serves to juxtapose components of the FGF signal transduction pathway.
Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells.
TLDR
A simple assay based on a genetically engineered soluble form of murine FGF receptor 1 tagged with placental alkaline phosphatase showed that FGF-receptor binding has an absolute requirement for heparin and facilitated FGF dimerization, a property that may be important for receptor activation.
...
...