title: Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization.
abstract: Two competing models for fibroblast growth factor (FGF) receptor (FGFR) dimerization have recently emerged based on ternary FGF-FGFR-heparin crystal structures. In the symmetric two-end model, heparin promotes dimerization of two FGF-FGFR complexes by stabilizing bivalent interactions of the ligand and receptor through primary and secondary sites and by stabilizing direct receptor-receptor contacts. In the asymmetric model, there are no protein-protein contacts between the two FGF-FGFR complexes, which are bridged solely by heparin. To identify the correct mode of FGFR dimerization, we abolished interactions at the secondary ligand-receptor interaction site, which are observed only in the symmetric two-end model, using site-directed mutagenesis. Cellular studies and real-time binding assays, as well as matrix-assisted laser desorption ionization-time of flight analysis, demonstrate that loss of secondary ligand-receptor interactions results in diminished FGFR activation due to decreased dimerization without affecting FGF-FGFR binding. Additionally, structural and biochemical analysis of an activating FGFR2 mutation resulting in Pfeiffer syndrome confirms the physiological significance of receptor-receptor contacts in the symmetric two-end model and provides a novel mechanism for FGFR gain of function in human skeletal disorders. Taken together, the data validate the symmetric two-end model of FGFR dimerization and argue against the asymmetric model of FGFR dimerization.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Brian K
authors.initials: BK
authors.lastname: Yeh
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Olsen
authors.forename: Makoto
authors.initials: M
authors.lastname: Igarashi
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance
chemical_list: D051526:Fibroblast Growth Factor 10; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D006493:Heparin; D051497:Receptor, Fibroblast Growth Factor, Type 2