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The Cap-snatching Endonuclease Of Influenza Virus Polymerase Resides In The Pa Subunit

机译：流感病毒聚合酶的帽捕捉核酸内切酶位于Pa亚基中

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摘要

The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type Ⅱ restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.
机译：流感病毒聚合酶是由三个亚基PA，PB1和PB2组成的异源三聚体，负责在感染细胞核中复制和转录病毒RNA基因组的八个独立片段。聚合酶利用独特的“帽锁扣”机制，使用源自细胞转录物的短帽引物合成病毒信使RNA。 PB2亚基结合宿主前mRNA的5'帽，随后被病毒内切核酸酶切割10-13个核苷酸，迄今为止被认为位于PB2（参考5）或PB1（参考2）亚基中。在这里，我们描述了生化和结构研究，表明PA亚基的氨基末端209个残基含有核酸内切酶活性位点。我们显示该域具有被锰离子强烈激活的内在RNA和DNA内切核酸酶活性，与完整三聚体聚合酶的内切核酸酶活性报道的观察结果相符。此外，该活性被2，4-二氧代-4-苯基丁酸（一种流行性感冒核酸内切酶抑制剂）抑制。该结构域的晶体结构揭示了一个结构核心，该结构核心与分辨酶和Ⅱ型限制性核酸内切酶非常相似。活性位点包含一个组氨酸和一个在所有流感病毒中都保守的三个酸性残基簇，它们以与其他依赖于两个金属的核酸内切酶相似的构型结合两个锰离子。先前已显示两个活性位点残基在突变时能特异性消除聚合酶核酸内切酶活性。这些结果将有助于优化核酸内切酶抑制剂作为潜在的新型抗流感药物。

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