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

Omar A. Ibrahimi, Brian K. Yeh, Anna V. Eliseenkova, Fuming Zhang, Shaun K. Olsen, Makoto Igarashi, Stuart A. Aaronson, Robert J. Linhardt, Moosa Mohammadi

Resultado de la investigación: Articlerevisión exhaustiva

49 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)671-684
Número de páginas14
PublicaciónMolecular and cellular biology
Volumen25
N.º2
DOI
EstadoPublished - ene. 2005
Publicado de forma externa

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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