Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK.
Mol Cell. 2018 Jun 21;70(6):1101-1110.e4. doi: 10.1016/j.molcel.2018.05.011. Epub 2018 Jun 14.
Influenza virus RNA polymerase (FluPol), a heterotrimer composed of PB1, PB2, and PA subunits (P3 in influenza C), performs both transcription and replication of the viral RNA genome. For transcription, FluPol interacts with the C-terminal domain (CTD) of RNA polymerase II (Pol II), which enables FluPol to snatch capped RNA primers from nascent host RNAs. Here, we describe the co-crystal structure of influenza C virus polymerase (FluPol) bound to a Ser5-phosphorylated CTD (pS-CTD) peptide. The position of the CTD-binding site at the interface of PB1, P3, and the flexible PB2 C-terminal domains suggests that CTD binding stabilizes the transcription-competent conformation of FluPol. In agreement, both cap snatching and capped primer-dependent transcription initiation by FluPol are enhanced in the presence of pS-CTD. Mutations of amino acids in the CTD-binding site reduce viral mRNA synthesis. We propose a model for the activation of the influenza virus transcriptase through its association with pS-CTD of Pol II.
流感病毒 RNA 聚合酶（FluPol）是一种由 PB1、PB2 和 PA 亚基（流感 C 中的 P3）组成的异三聚体，可执行病毒 RNA 基因组的转录和复制。对于转录，FluPol 与 RNA 聚合酶 II（Pol II）的 C 端结构域（CTD）相互作用，使 FluPol 能够从新生宿主 RNA 中抢夺加帽 RNA 引物。在这里，我们描述了结合有 Ser5 磷酸化 CTD（pS-CTD）肽的流感 C 病毒聚合酶（FluPol）的共晶结构。CTD 结合位点在 PB1、P3 和灵活的 PB2 C 端结构域界面上的位置表明 CTD 结合稳定了 FluPol 的转录活性构象。一致地，在存在 pS-CTD 的情况下，FluPol 的帽抢夺和加帽引物依赖性转录起始均增强。CTD 结合位点上氨基酸的突变会降低病毒 mRNA 的合成。我们提出了一种通过与 Pol II 的 pS-CTD 结合来激活流感病毒转录酶的模型。
