title: Effect of the achondroplasia mutation on FGFR3 dimerization and FGFR3 structural response to fgf1 and fgf2: A quantitative FRET study in osmotically derived plasma membrane vesicles.
abstract: The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative Fӧster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations. Instead, the most notable effect of the achondroplasia mutation is increased propensity for FGFR3 dimerization in the absence of ligand. This work reveals new information about the molecular events that underlie the achondroplasia phenotype, and highlights differences in FGFR3 activation due to different single amino-acid pathogenic mutations.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
authors.forename: Sarvenaz
authors.initials: S
authors.lastname: Sarabipour
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States. Electronic address: kh@jhu.edu.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D000130:Achondroplasia / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003412:Cricetulus; D000067128:Extracellular Vesicles / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009995:Osmosis; D011485:Protein Binding; D055503:Protein Multimerization; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D008024:Ligands; D008164:Luminescent Proteins; D051498:Receptor, Fibroblast Growth Factor, Type 3; D000097573:Red Fluorescent Protein; C054562:yellow fluorescent protein, Bacteria; C496365:FGFR3 protein, human
keywords: Achondroplasia; Dimer stability; Dimerization; Fibroblast growth factor receptor 3; Receptor tyrosine kinases; skeletal disorders