Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins.
Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins.
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DOI：
10.1038/nature11783
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发表时间：
2013-02-07
期刊：
影响因子：
64.8
通讯作者：
Nagar B
中科院分区：
文献类型：
--
作者：
Abbas YM;Pichlmair A;Górna MW;Superti-Furga G;Nagar B
干扰素诱导的三肽重复序列蛋白（IFIT）是一种先天性免疫效应分子，通过破坏宿主免疫启动机制中的蛋白质-蛋白质相互作用而发挥抗病毒防御作用。然而，最近发现IFIT可以直接识别带有5′-三磷酸基团（PPP-RNA）的病毒RNA，这是将其与宿主RNA区分开的分子特征。在这里，我们报告的晶体结构的人IFIT 5，其复杂的PPP-RNA，和一个氨基末端片段的IFIT 1。这些结构揭示了一个新的螺旋结构域，其中包含一个带正电荷的空腔，该空腔设计用于仅特异性地接合单链PPP-RNA，从而将其与双链病毒PPP-RNA的典型胞质传感器视黄酸诱导基因I（RIG-I，也称为DDX 58）区分开来。突变分析、蛋白水解和凝胶迁移分析表明PPP-RNA以非序列特异性方式结合，需要约3个核苷酸的5′-突出端。发现IFIT 1和IFIT 5中PPP-RNA结合的消除导致人胚肾细胞的抗病毒应答缺陷。这些结果证明了IFIT蛋白选择性识别病毒RNA的机制，并深入了解其下游效应子功能。本文的在线版本（doi：10.1038/nature 11783）包含补充材料，可供授权用户使用。晶体结构揭示了干扰素诱导的蛋白质与tetratricopeptide repeats（IFIT）如何选择性地识别病毒RNA。本文的在线版本（doi：10.1038/nature 11783）包含补充材料，可供授权用户使用。IFIT-干扰素诱导的蛋白与tetratricopeptide重复-是先天免疫系统的抗病毒成分。最近的工作表明，它们可能作为RNA传感器，在这项研究中，Bhushan Nagar和同事阐明了特异性识别三磷酸化病毒RNA（PPP-RNA）的结构基础。人IFIT 5的晶体结构、其与PPP-RNA的复合物以及IFIT 1的氨基末端片段揭示了三磷酸基团整齐地适合于蛋白质内的深口袋，该蛋白质还容纳RNA的前三个核苷酸。本文的在线版本（doi：10.1038/nature 11783）包含补充材料，可供授权用户使用。
Interferon-induced proteins with tetratricopeptide repeats (IFITs) are innate immune effector molecules that are thought to confer antiviral defence through disruption of protein–protein interactions in the host translation-initiation machinery. However, it was recently discovered that IFITs can directly recognize viral RNA bearing a 5′-triphosphate group (PPP-RNA), which is a molecular signature that distinguishes it from host RNA. Here we report crystal structures of human IFIT5, its complex with PPP-RNAs, and an amino-terminal fragment of IFIT1. The structures reveal a new helical domain that houses a positively charged cavity designed to specifically engage only single-stranded PPP-RNA, thus distinguishing it from the canonical cytosolic sensor of double-stranded viral PPP-RNA, retinoic acid-inducible gene I (RIG-I, also known as DDX58). Mutational analysis, proteolysis and gel-shift assays reveal that PPP-RNA is bound in a non-sequence-specific manner and requires a 5′-overhang of approximately three nucleotides. Abrogation of PPP-RNA binding in IFIT1 and IFIT5 was found to cause a defect in the antiviral response by human embryonic kidney cells. These results demonstrate the mechanism by which IFIT proteins selectively recognize viral RNA, and lend insight into their downstream effector function. The online version of this article (doi:10.1038/nature11783) contains supplementary material, which is available to authorized users. Crystal structures reveal insight into how interferon-induced proteins with tetratricopeptide repeats (IFITs) selectively recognize viral RNA. The online version of this article (doi:10.1038/nature11783) contains supplementary material, which is available to authorized users. IFITs — interferon-induced proteins with tetratricopeptide repeats — are antiviral components of the innate immune system. Recent work suggested that they may act as RNA sensors, and in this study Bhushan Nagar and colleagues elucidate the structural basis for the specific recognition of triphosphorylated viral RNA (PPP-RNA). The crystal structures of human IFIT5, its complex with PPP-RNAs, and an amino-terminal fragment of IFIT1 reveal that the triphosphate group fits neatly into a deep pocket within the protein, which also accommodates the first three nucleotides of the RNA. The online version of this article (doi:10.1038/nature11783) contains supplementary material, which is available to authorized users.