Structure-based mutational analyses in FGF7 identify new residues involved in specific interaction with FGFR2IIIb.
Receptor binding specificity is an essential element in regulating the diverse activities of fibroblast growth factors (FGFs). FGF7 is ideal to study how this specificity is conferred at the structural level, as it interacts exclusively with one isoform of the FGF-receptor (FGFR) family, known as FGFR2IIIb. Previous mutational analysis suggested the importance of the beta4/beta5 loop of FGF7 in specific receptor recognition. Here a theoretical model of FGFR2IIIb/FGF7 complex showed that this loop interacts with the FGFR2IIIb unique exon. In addition, the model revealed new residues that either directly interact with the FGFR2IIIb unique exon (Asp63, Leu142) or facilitate this interaction (Arg65). Mutations in these residues reduced both receptor binding affinity and biological activity of FGF7. Altogether, these results provide the basis for understanding how receptor-binding specificity of FGF7 is conferred at the structural level.
Sher
Ifat
I
Department of Biology, Technion - Israel Institute of Technology, 32000 Haifa, Israel.
Yeh
Brian K
BK
Mohammadi
Moosa
M
Adir
Noam
N
Ron
Dina
D
D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005091:Exons; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism*
C496454:Fgf7 protein, mouse; D046911:Macromolecular Substances; D017468:Receptors, Fibroblast Growth Factor; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2