Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
Science. 2020 Feb 7;367(6478):643-652. doi: 10.1126/science.aaw3242.
Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.
同源二聚体 I 类细胞因子受体被认为以前体二聚体的形式存在，通过配体诱导的构象变化而被激活。我们通过单分子荧光显微镜定量测量了三种典型的 I 类细胞因子受体在活细胞质膜中的二聚化。单个受体亚基的空间和时空相关性显示出配体诱导的二聚化，并揭示了相关的 Janus 激酶 2（JAK2）通过其假激酶结构域二聚化。致癌受体和高活性 JAK2 突变体促进了配体非依赖性二聚化，突出了受体二聚体的形成作为负责信号激活的开关。基于对二聚化涉及的相互作用进行详细能量分析的原子建模和分子动力学模拟，为同源二聚体 I 类细胞因子受体的激活及其由单个突变引起的失调提供了一种机制蓝图。
