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Genes Cells. 2015 Oct;20(10):860-70. doi: 10.1111/gtc.12277. Epub 2015 Aug 24.

Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain.

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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.
Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.


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.

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