title: The A391E mutation enhances FGFR3 activation in the absence of ligand.
abstract: 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.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Fenghao
authors.initials: F
authors.lastname: Chen
authors.forename: Catherine
authors.initials: C
authors.lastname: Degnin
authors.forename: Melanie
authors.initials: M
authors.lastname: Laederich
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D055550:Protein Stability; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D008024:Ligands; D016220:Fibroblast Growth Factor 1; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3