title: Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain.
abstract: Receptor and nonreceptor tyrosine kinases are enzymes that play important roles in regulating signal transduction pathways in a variety of normal cellular process and in many pathological conditions. Ordered phosphorylation is required for receptor tyrosine kinase (RTK) activation, a process mediated by transient dimer formation of the kinase domains. This process is triggered by the tyrosine phosphorylation in the activation loop. Here, we report structural and biochemical analyses of the tyrosine kinase domain interaction of fibroblast growth factor receptor 1 (FGFR1) required for the initial phosphorylation step. On the basis of nuclear magnetic resonance (NMR) analysis and covalent cross-linking experiments, we propose a parallel symmetric dimer model where specific contacts are formed between the N-lobes and C-lobes, respectively, in the FGFR1 kinase domains. Moreover, assignment of the contact sites between two FGFR1 kinase domains are supported by a trans-phosphorylation assay and by mutational analyses. The present report shows the molecular mechanism underlying the control of trans-phosphorylation of a critical auto-regulatory site in FGF receptors' catalytic domain.
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.|Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Yoshihiro
authors: Y
authors: Kobashigawa
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Shinjiro
authors: S
authors: Amano
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Mariko
authors: M
authors: Yokogawa
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Hiroyuki
authors: H
authors: Kumeta
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Hiroshi
authors: H
authors: Morioka
authors: Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
authors: Masayori
authors: M
authors: Inouye
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors: Joseph
authors: J
authors: Schlessinger
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
authors: Fuyuhiko
authors: F
authors: Inagaki
mesh_terms: D006706:Homeostasis; D006801:Humans; D008279:Magnetic Resonance Imaging; D062105:Molecular Docking Simulation; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1