Escalante Carlos R, Nistal-Villán Estanislao, Shen Leyi, García-Sastre Adolfo, Aggarwal Aneel K
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Mol Cell. 2007 Jun 8;26(5):703-16. doi: 10.1016/j.molcel.2007.04.022.
Interferon regulatory factor 3 (IRF-3) is a key transcription factor in the assembly of the mammalian interferon-beta (IFN-beta) enhanceosome. We present here the structure of IRF-3 DNA binding domain in complex with the complete PRDIII-I regulatory element of the human IFN-beta enhancer. We show that four IRF-3 molecules bind in tandem to, variably spaced, consensus and nonconsensus IRF sites on the composite element. The ability of IRF-3 to bind these variable sites derives in part from two nonconserved arginines (Arg78 and Arg86) that partake in alternate protein-DNA contacts. We also show that the protein-DNA contacts are highly overlapped and that all four IRF sites are required for gene activation in vivo. In addition, we show that changing the nonconsensus IRF sites to consensus sites creates a more efficient enhancer in vivo. Together, the structure and accompanying biological data provide insights into the assembly of the IFN-beta enhanceosome in mammals.
干扰素调节因子3（IRF-3）是哺乳动物干扰素-β（IFN-β）增强体组装中的关键转录因子。我们在此展示了与人类IFN-β增强子完整的PRDIII-I调节元件复合的IRF-3 DNA结合结构域的结构。我们发现四个IRF-3分子串联结合在复合元件上可变间距的共有和非共有IRF位点上。IRF-3结合这些可变位点的能力部分源自两个非保守精氨酸（精氨酸78和精氨酸86），它们参与不同的蛋白质-DNA接触。我们还表明蛋白质-DNA接触高度重叠，并且所有四个IRF位点在体内基因激活中都是必需的。此外，我们发现将非共有IRF位点改变为共有位点可在体内产生更有效的增强子。这些结构和相关生物学数据共同为哺乳动物中IFN-β增强体的组装提供了见解。
