Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells
Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells
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DOI：
10.1073/pnas.0914157107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Schlessinger, Joseph
中科院分区：
文献类型：
--
作者：
Bae, Jae Hyun;Boggon, Titus J.;Schlessinger, Joseph
受体酪氨酸激酶的酪氨酸自磷酸化在激酶活性的调节以及细胞内信号通路的募集和激活中起关键作用。自磷酸化是由一个连续的和精确有序的分子间（反式）反应介导的。在这份报告中，我们提出的结构和生化实验表明，激活的FGFR1激酶结构域之间的不对称二聚体的形成是必需的FGFR1在FGF刺激的细胞转磷酸化。转磷酸化是由一个激酶分子的N端半叶（作为活性酶）和第二个激酶分子的C端半叶（作为底物）上的特异性对接位点之间的特异性不对称接触介导的。在这个界面中的病理性功能丧失突变或致癌激活突变可能分别阻碍或促进不对称二聚体形成和转磷酸化。本报告中提出的实验提供了FGF受体和其他受体酪氨酸激酶的转磷酸化控制的分子基础。
Tyrosine autophosphorylation of receptor tyrosine kinases plays a critical role in regulation of kinase activity and in recruitment and activation of intracellular signaling pathways. Autophosphorylation is mediated by a sequential and precisely ordered intermolecular (trans) reaction. In this report we present structural and biochemical experiments demonstrating that formation of an asymmetric dimer between activated FGFR1 kinase domains is required for transphosphorylation of FGFR1 in FGF-stimulated cells. Transphosphorylation is mediated by specific asymmetric contacts between the N-lobe of one kinase molecule, which serves as an active enzyme, and specific docking sites on the C-lobe of a second kinase molecule, which serves a substrate. Pathological loss-of-function mutations or oncogenic activating mutations in this interface may hinder or facilitate asymmetric dimer formation and transphosphorylation, respectively. The experiments presented in this report provide the molecular basis underlying the control of transphosphorylation of FGF receptors and other receptor tyrosine kinases.