Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1.
The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR-ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1-Ig2 interaction. The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module overlaps the Ig2-Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR-ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2-Ig2 interaction) in the absence of FGF.
Kiselyov
Vladislav V
VV
Protein Laboratory, Institute of Molecular Pathology, Copenhagen DK-2200, Denmark.
Kochoyan
Arthur
A
Poulsen
Flemming M
FM
Bock
Elisabeth
E
Berezin
Vladimir
V
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D019281:Dimerization; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance
D007136:Immunoglobulins; D008024:Ligands; D005346:Fibroblast Growth Factors; D006493:Heparin; D051496:Receptor, Fibroblast Growth Factor, Type 1