European Molecular Biology Laboratory, 38042 Grenoble, France.
CRCHUM-Research Center, Centre Hospitalier de l'Université de Montréal, Montréal, H2X0A9, QC, Canada.
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E601-E609. doi: 10.1073/pnas.1718426115. Epub 2018 Jan 9.
Cytokine signaling through the JAK/STAT pathway controls multiple cellular responses including growth, survival, differentiation, and pathogen resistance. An expansion in the gene regulatory repertoire controlled by JAK/STAT signaling occurs through the interaction of STATs with IRF transcription factors to form ISGF3, a complex that contains STAT1, STAT2, and IRF9 and regulates expression of IFN-stimulated genes. ISGF3 function depends on selective interaction between IRF9, through its IRF-association domain (IAD), with the coiled-coil domain (CCD) of STAT2. Here, we report the crystal structures of the IRF9-IAD alone and in a complex with STAT2-CCD. Despite similarity in the overall structure among respective paralogs, the surface features of the IRF9-IAD and STAT2-CCD have diverged to enable specific interaction between these family members. We derive a model for the ISGF3 complex bound to an ISRE DNA element and demonstrate that the observed interface between STAT2 and IRF9 is required for ISGF3 function in cells.
通过 JAK/STAT 途径的细胞因子信号转导控制多种细胞反应，包括生长、存活、分化和病原体抗性。JAK/STAT 信号转导控制的基因调控谱的扩展是通过 STATs 与 IRF 转录因子相互作用形成 ISGF3 来实现的，ISGF3 复合物包含 STAT1、STAT2 和 IRF9，并调节 IFN 刺激基因的表达。ISGF3 的功能取决于 IRF9 通过其 IRF 结合域 (IAD) 与 STAT2 的卷曲螺旋结构域 (CCD) 之间的选择性相互作用。在这里，我们报告了 IRF9-IAD 及其与 STAT2-CCD 复合物的晶体结构。尽管各自的同源蛋白在整体结构上具有相似性，但 IRF9-IAD 和 STAT2-CCD 的表面特征已经分化，以实现这些家族成员之间的特异性相互作用。我们得出了一个结合 ISRE DNA 元件的 ISGF3 复合物的模型，并证明了 STAT2 和 IRF9 之间观察到的界面是 ISGF3 在细胞中发挥功能所必需的。
