Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2011 Aug 19;146(4):621-32. doi: 10.1016/j.cell.2011.06.048.
Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor points" interspersed among ligand-specific interactions that "tune" the relative IFN-binding affinities, in an apparent extracellular "ligand proofreading" mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.
I 型干扰素（IFNs）是先天抗病毒和抗癌免疫的重要细胞因子。16 种人类 I 型 IFN 变体通过相同的细胞表面受体 IFNAR1 和 IFNAR2 发出信号，但它们可以引起明显不同的生理效应。两种包含 IFNα2 和 IFNω 的人 I 型 IFN 三元信号复合物的晶体结构揭示了识别模式和异三聚体结构，这些在细胞因子受体超家族中是独特的，但在不同的 I 型 IFN 之间是保守的。受体重组配体交叉反应是由配体特异性相互作用之间的保守受体配体“锚定点”启用的，这些“调节”相对 IFN 结合亲和力，在一种明显的细胞外“配体校对”机制中，调节生物活性。IFNs 之间的功能差异与其各自的受体识别化学性质有关，与 IFNAR1 中的配体诱导构象变化协同作用，共同控制信号起始和复合物稳定性，最终调节差异 STAT 磷酸化谱、受体内化率和下游基因表达模式。
