title: Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization.
abstract: Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise because of five different mutations, all involving the substitution of an amino acid with a cysteine in fibroblast growth factor receptor 3 (FGFR3). Cysteine mutations in receptor tyrosine kinases (RTKs) have been previously proposed to induce constitutive dimerization in the absence of ligand, leading to receptor overactivation. However, their effect on RTK dimer stability has never been measured experimentally. In this study, we characterize the effect of three TDI mutations, Arg248Cys, Ser249Cys, and Tyr373Cys, on FGFR3 dimerization in mammalian membranes, in the absence of ligand. We demonstrate that the mutations lead to surprisingly modest dimer stabilization and to structural perturbations of the dimers, challenging the current understanding of the molecular interactions that underlie TDI.
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Nuala
authors.initials: N
authors.lastname: Del Piccolo
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jesse
authors.initials: J
authors.lastname: Placone
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland. Electronic address: kh@jhu.edu.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D020125:Mutation, Missense; D055503:Protein Multimerization; D055550:Protein Stability; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013796:Thanatophoric Dysplasia / Q000235:genetics*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3