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Biochim Biophys Acta. 2011 Aug;1808(8):2045-50. doi: 10.1016/j.bbamem.2011.04.007. Epub 2011 Apr 22.

The A391E mutation enhances FGFR3 activation in the absence of ligand.

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  • 1Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.


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.

Copyright © 2011 Elsevier B.V. All rights reserved.

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