Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs

Biochemistry. 2001 Dec 4;40(48):14429-39. doi: 10.1021/bi011000u.


Stromal cell-derived FGF-7 binds and activates only the resident FGFR2IIIb in epithelial cells while FGF-1 and FGF-2 exhibit a broader interaction with multiple isoforms of FGFR. Here we report the structure of FGF-7 that has been solved to 3.1 A resolution by molecular replacement with the structure of a dual function chimera of FGF-7 and FGF-1 (FGF-7/1) which was resolved to 2.3 A. Comparison of the FGF-7 structure to that of FGF-1 and FGF-2 revealed the strongly conserved Calpha backbone among the three FGF polypeptides and the surface hydrophobic patch that forms the primary receptor-binding domain. In contrast, a decrease and dispersion of the positive surface charge density characterized the heparin-binding domain of FGF-7 defined by homology to that of FGF-1 and FGF-2 in complexes with heparin. A simple heparin hexasaccharide that cocrystallized with FGF-1 and FGF-2 and protected both against protease in solution failed to exhibit the same properties with FGF-7. In contrast to FGF-1 and FGF-2, protection of FGF-7 was enhanced by heparin oligosaccharides of increased length with those exhibiting a 3-O-sulfate being the most effective. Protection of FGF-7 required interaction with specifically the fraction of crude heparin retained on antithrombin affinity columns. Conversely, heparin enriched by affinity for immobilized FGF-7 exhibited anti-factor Xa activity similar to that purified on an antithrombin affinity matrix. In contrast, an FGF-1 affinity matrix enriched the fraction of crude heparin with low anti-factor Xa activity. The results provide a structural basis to suggest that the unique FGF-7 heparin-binding (HB) domain underlies a specific restriction in respect to composition and length of the heparan sulfate motif that may impact specificity of localization, stability, and trafficking of FGF-7 in the microenvironment, and formation and activation of the FGFR2IIIb kinase signaling complex in epithelial cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Crystallization
  • Factor Xa / immunology
  • Factor Xa / metabolism
  • Fibroblast Growth Factor 1 / chemistry
  • Fibroblast Growth Factor 1 / metabolism*
  • Fibroblast Growth Factor 2 / chemistry
  • Fibroblast Growth Factor 2 / metabolism*
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors / chemistry
  • Fibroblast Growth Factors / metabolism*
  • Heparin / pharmacology
  • Heparitin Sulfate / metabolism*
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 1
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors
  • Heparin
  • Heparitin Sulfate
  • Factor Xa

Associated data

  • PDB/1QQK
  • PDB/1QQL