Activated by interaction Cytokines trigger immune responses when they bind to their cognate receptors. Class I cytokine receptors rely on the associated Janus kinase 2 (JAK2) to initiate signal transduction. There has been debate over whether activation involves ligand-induced dimerization of these receptors or ligand-induced conformational change of preformed dimers. Wilmes et al. imaged cytokine receptors in the plasma membranes of live human cells by single-molecule fluorescence microscopy and observed ligand-induced dimerization. They found that the JAK2 pseudokinase domains contribute to dimerization and that hyperactive JAK2 mutants promote dimerization, consistent with the model that dimerization triggers activation. Science, this issue p. 643 Class 1 cytokine receptors are activated by ligand-induced dimerization. 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.

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致癌突变引起同源二聚体细胞因子受体激活和失调的机制

通过相互作用激活细胞因子在与其同源受体结合时会触发免疫反应。I 类细胞因子受体依赖于相关的 Janus 激酶 2 (JAK2) 来启动信号转导。关于激活是否涉及这些受体的配体诱导的二聚化或预先形成的二聚体的配体诱导的构象变化一直存在争议。威尔姆斯等人。通过单分子荧光显微镜对活人细胞质膜中的细胞因子受体进行成像，并观察到配体诱导的二聚化。他们发现 JAK2 假激酶结构域有助于二聚化，而过度活跃的 JAK2 突变体促进二聚化，这与二聚化触发激活的模型一致。科学，这个问题 p。643 1 类细胞因子受体被配体诱导的二聚化激活。假设同型二聚体 I 类细胞因子受体以预先形成的二聚体形式存在，这些二聚体被配体诱导的构象变化激活。我们通过单分子荧光显微镜量化了活细胞质膜中三种原型 I 类细胞因子受体的二聚化。单个受体亚基的空间和时空相关性显示配体诱导的二聚化，并揭示相关的 Janus 激酶 2 (JAK2) 通过其假激酶结构域二聚化。致癌受体和过度活跃的 JAK2 突变体促进了不依赖配体的二聚化，突出了受体二聚体的形成作为负责信号激活的开关。