title: The achondroplasia mutation does not alter the dimerization energetics of the fibroblast growth factor receptor 3 transmembrane domain.
abstract: The Gly380 --> Arg mutation in the TM domain of fibroblast growth factor receptor 3 (FGFR3) of the RTK family is linked to achondroplasia, the most common form of human dwarfism. The molecular mechanism of pathology induction is under debate, and two different mechanisms have been proposed to contribute to pathogenesis: (1) Arg380-mediated FGFR3 dimer stabilization and (2) slow downregulation of the activated mutant receptors. Here we show that the Gly380 --> Arg mutation does not alter the dimerization energetics of the FGFR3 transmembrane domain in detergent micelles or in lipid bilayers. This result indicates that pathogenesis in achondroplasia cannot be explained simply by a higher dimerization propensity of the mutant FGFR3 TM domain, thus highlighting the importance of the observed slow downregulation in phenotype induction.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Min
authors.initials: M
authors.lastname: You
authors.forename: Edwin
authors.initials: E
authors.lastname: Li
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D000130:Achondroplasia / Q000209:etiology / Q000235:genetics*; D000595:Amino Acid Sequence; D002942:Circular Dichroism; D019281:Dimerization; D015536:Down-Regulation; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008823:Micelles; D008969:Molecular Sequence Data; D017354:Point Mutation; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*
chemical_list: D008051:Lipid Bilayers; D008823:Micelles; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3