Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization.
The epithelial fibroblast growth factor 9 (FGF9) subfamily specifically binds and activates the mesenchymal "c" splice isoform of FGF receptors 1-3 (FGFR1-3) to regulate organogenesis and tissue homeostasis. The unique N and C termini of FGF9 subfamily ligands mediate a reversible homodimerization that occludes major receptor binding sites within the ligand core region. Here we provide compelling X-ray crystallographic, biophysical, and biochemical data showing that homodimerization controls receptor binding specificity of the FGF9 subfamily by keeping the concentration of active FGF9 monomers at a level, which is sufficient for a normal FGFR "c" isoform binding/signaling, but is insufficient for an illegitimate FGFR "b" isoform binding/signaling. We show that deletion of the N terminus or alanine substitutions in the C terminus of FGF9 skews the delicate ligand equilibrium toward active FGF9 monomers causing off-target binding and activation of FGFR b isoforms. Our study is the first to implicate ligand homodimerization in the regulation of ligand-receptor specificity.
['Liu|Yang|Y|', 'Ma|Jinghong|J|', 'Beenken|Andrew|A|', 'Srinivasan|Lakshmi|L|', 'Eliseenkova|Anna V|AV|', 'Mohammadi|Moosa|M|']
D001665:Binding Sites D018360:Crystallography, X-Ray D051525:Fibroblast Growth Factor 9 D005786:Gene Expression Regulation D057809:HEK293 Cells D006801:Humans D008958:Models, Molecular D009154:Mutation D011485:Protein Binding D055503:Protein Multimerization D017468:Receptors, Fibroblast Growth Factor
specificity homodimerization fibroblast growth factor 9 FGF receptor 1 BaF3 cells X-ray crystallography autoinhibition multi-angle light scattering surface plasmon resonance