Role of the N-Terminal Transmembrane Helix Contacts in the Activation of FGFR3
Role of the N-Terminal Transmembrane Helix Contacts in the Activation of FGFR3
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DOI：
10.1002/jcc.26122
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发表时间：
2019-12-05
影响因子：
3
通讯作者：
Sugita, Yuji
中科院分区：
文献类型：
--
作者：
Matsuoka, Daisuke;Kamiya, Motoshi;Sugita, Yuji
成纤维细胞生长因子受体3（FGFR3）是受体酪氨酸激酶的成员，其参与骨骼细胞的生长、分化和迁移。FGFR3通过跨膜（TM）螺旋二聚体的构象变化将生化信号从胞外配体结合结构域转导至胞内激酶结构域。在这里，我们将广义副本交换与溶质回火方法应用于FGFR 3的野生型（WT）和G380 R突变体（G380 R）。G380R中的二聚体界面与WT中的不同，模拟结果与固体核磁共振（NMR）谱吻合良好。G380 R中的TM螺旋比WT延伸更多，因此，G380 R中的G375在TM螺旋二聚体的N末端附近接触。考虑到G380 R和G375 C都显示出组成性活化，TM螺旋的N-末端接触的形成通常对于活化机制是重要的。(c)2019 Wiley Periodicals，Inc.
Fibroblast growth factor receptor 3 (FGFR3) is a member of receptor tyrosine kinases, which is involved in skeletal cell growth, differentiation, and migration. FGFR3 transduces biochemical signals from the extracellular ligand-binding domain to the intracellular kinase domain through the conformational changes of the transmembrane (TM) helix dimer. Here, we apply generalized replica exchange with solute tempering method to wild type (WT) and G380R mutant (G380R) of FGFR3. The dimer interface in G380R is different from WT and the simulation results are in good agreement with the solid-state nuclear magnetic resonance (NMR) spectroscopy. TM helices in G380R are extended more than WT, and thereby, G375 in G380R contacts near the N-termini of the TM helix dimer. Considering that both G380R and G375C show the constitutive activation, the formation of the N-terminal contacts of the TM helices can be generally important for the activation mechanism. (c) 2019 Wiley Periodicals, Inc.