title: Role of dimerization efficiency of transmembrane domains in activation of fibroblast growth factor receptor 3.
abstract: Mutations in transmembrane (TM) domains of receptor tyrosine kinases are shown to cause a number of inherited diseases and cancer development. Here, we use a combined molecular modeling approach to understand molecular mechanism of effect of G380R and A391E mutations on dimerization of TM domains of human fibroblast growth factor receptor 3 (FGFR3). According to results of Monte Carlo conformational search in the implicit membrane and further molecular dynamics simulations, TM dimer of this receptor is able to form a number of various conformations, which differ significantly by the free energy of association in a full-atom model bilayer. The aforementioned mutations affect dimerization efficiency of TM segments and lead to repopulation of conformational ensemble for the dimer. Particularly, both mutations do not change the dimerization free energy of the predominant (putative "non-active") symmetric conformation of TM dimer, while affect dimerization efficiency of its asymmetric ("intermediate") and alternative symmetric (putative "active") models. Results of our simulations provide novel atomistic prospective of the role of G380 and A391E mutations in dimerization of TM domains of FGFR3 and their consecutive contributions to the activation pathway of the receptor.
authors.affiliation: M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences , Moscow, 117997, Russia.
authors.forename: Pavel E
authors.initials: PE
authors.lastname: Volynsky
authors.forename: Anton A
authors.initials: AA
authors.lastname: Polyansky
authors.forename: Gulfia N
authors.initials: GN
authors.lastname: Fakhrutdinova
authors.forename: Eduard V
authors.initials: EV
authors.lastname: Bocharov
authors.forename: Roman G
authors.initials: RG
authors.lastname: Efremov
mesh_terms: D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D009154:Mutation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3