Journal
BIOCHEMISTRY
Volume 40, Issue 48, Pages 14429-14439Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi011000u
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Funding
- NCI NIH HHS [CA59971] Funding Source: Medline
- NHLBI NIH HHS [HL52622] Funding Source: Medline
- NIDDK NIH HHS [DK35310, DK47039] Funding Source: Medline
- NIGMS NIH HHS [GM38060] Funding Source: Medline
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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 Angstrom. Comparison of the FGF-7 structure to that of FGF-1 and FGF-2 revealed the strongly conserved Ca 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.
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