1qql
|
THE CRYSTAL STRUCTURE OF FIBROBLAST GROWTH FACTOR 7/1 CHIMERA
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Aplasia of lacrimal and salivary glands OMIM:[602115], LADD syndrome OMIM:[602115]
About this StructureAbout this Structure
1QQL is a Single protein structure of sequence from Rattus norvegicus + homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs., Ye S, Luo Y, Lu W, Jones RB, Linhardt RJ, Capila I, Toida T, Kan M, Pelletier H, McKeehan WL, Biochemistry. 2001 Dec 4;40(48):14429-39. PMID:11724555
Page seeded by OCA on Mon Nov 12 18:55:36 2007