FGF Receptor Dimer Structure Analyzed

Science's STKE  18 Jan 2005:
Vol. 2005, Issue 267, pp. tw27
DOI: 10.1126/stke.2672005tw27

The fibroblast growth factor receptor, like other receptor tyrosine kinases, forms activated dimers. Crystal structures of the receptor with FGF with and without heparin sulfate proteoglycan (HSPG), which helps promote dimerization, have led to two distinct hypotheses for the structure of the receptor dimer. In one model, the complex is symmetric and has two interaction sites between ligand and receptor as well as a direct receptor-receptor interaction site, all of which are stabilized by heparin. The assymetric model suggests that the two receptor molecules have no contacts and are bridged by heparin. Ibrahimi et al. attempted to distinguish between the two models by monitoring the effects of mutations in the distinct interfaces that form the proposed interaction surfaces in the two models. They then monitored ligand binding by surface plasmon resonance, biological effects with assays of cell proliferation, and receptor dimerization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. A gain-of-function mutation in FGFR2 that causes developmental defects known as Pfeiffer's syndrome in humans is predicted in the symmetric model to stabilize receptor dimers, and this was confirmed in the experimental studies. Likewise, disruption of ligand-receptor interfaces that are implicated only in the symmetric model decreased dimerization without altering FGF binding. Thus, the results favor the symmetric mode of interaction and provide a molecular mechanism for effects of FGF in a human disease.

O. A. Ibrahimi, B. K. Yeh, A. V. Eliseenkova, F. Zhang, S. K. Olsen, M. Igarashi, S. A. Aaronson, R. J. Linhardt, M. Mohammadi, 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. Mol. Cell Biol. 25, 671-684 (2005). [Abstract] [Full Text]