Mechanism of FGF receptor dimerization and activation.

Sarvenaz Sarabipour,Kalina Hristova

doi:10.1038/ncomms10262

Abstract

Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation. The pathogenic A391E mutation in FGFR3 TM domain emulates the action of fgf2, trapping the FGFR3 dimer in its most active state. This study establishes the existence of multiple active ligand-bound states, and uncovers a novel molecular mechanism through which FGFR-linked pathologies can arise.

Highlights

Fibroblast growth factors are widely believed to activate their receptors by mediating receptor dimerization
To gain insight into these issues, here we study the dimerization of FGFR1, FGFR2 and FGFR3, as well as the response of these receptors to the ligands fgf[1] and fgf[2]
To investigate the biological significance of the two different ligandbound states that we observed in the QI-Forster resonance energy transfer (FRET) experiments, we compared the phosphorylation of full-length FGFR1, FGFR2 and FGFR3 at saturating fgf[1] or fgf[2] concentrations (5 mg ml À 1) using western blotting

Summary

Introduction

Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. By comparing the intrinsic FRET in the presence and absence of ligand, here we investigated structural changes that occur on the cytoplasmic side of the receptor on ligand binding to the extracellular domains. Since the fluorescent proteins were attached directly to the TM domains via the flexible linker, we could directly monitor changes in the structure of the TM domains in the receptor dimers in response to ligand binding.

Results

Conclusion