The A391E mutation enhances FGFR3 activation in the absence of ligand

The A391E mutation in the transmembrane domain of fibroblast growth factor receptor 3 leads to aberrant development of the cranium. It has been hypothesized that the mutant glutamic acid stabilizes the dimeric receptor due to hydrogen bonding and enhances its ligand-independent activation. We previously tested this hypothesis in lipid bilayers and showed that the mutation stabilizes the isolated transmembrane domain dimer by − 1.3 ° kcal/mol. Here we further test the hypothesis, by investigating the effect of the A391E mutation on the activation of full-length fibroblast growth factor receptor 3 in Human Embryonic Kidney 293T cells in the absence of ligand. We find that the mutation enhances the ligand-independent activation propensity of the receptor by − 1.7 ° kcal/mol. This value is consistent with the observed strength of hydrogen bonds in membranes, and supports the above hypothesis.

Research highlights
► The plasma membrane expression of the A391E mutant is lower than the wild-type FGFR3 surface expression in HEK 293T cells.
► The A391E mutation increases the activation propensity of full-length FGFR3 in the absence of ligand by –1.7 kcal/mole.
► Pathogenesis due to the A391E FGFR3 mutation is likely linked to disregulation of ligand-independent activation.