Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport.
Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport.
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Sarbecovirus ORF6介导的核细胞质运输阻断的结构基础
DOI：
10.1038/s41467-022-32489-5
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发表时间：
2022-08-15
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
严重变异的SARS-CoV-2关注变体（VOCs）的出现使国际社会处于高度警惕状态。除了在VOCs刺突蛋白中定位的大量突变外，病毒附属蛋白ORF6和ORF9b的表达也升高；两者都是有效的干扰素拮抗剂。本文研究了Rae1-Nup98与SARS-CoV-2和SARS-CoV ORF6的c端尾（CTT）复合物的晶体结构，分辨率分别为2.85 Å和2.39 Å。ORF6 CTT的不变蛋氨酸(M) 58残基将其侧链延伸到Rae1 mRNA结合槽中的疏水腔中，类似于螺栓连接孔；M58两侧的酸性残基与Rae1形成盐桥。我们的诱变研究确定了ORF6在体外和细胞中与Rae1-Nup98相互作用的重要关键残基，其中M58是不可替代的。此外，我们发现ORF6介导的mRNA和STAT1核质转运的阻断与ORF6和Rae1-Nup98之间的结合亲和力有关。最后，ORF6与Rae1-Nup98的结合与ORF6诱导的干扰素拮抗作用有关。综上所述，本研究揭示了Sarbecovirus ORF6拮抗功能的分子基础，并暗示了利用ORF6 ctt衍生肽开发免疫抑制药物的策略。Sarbecovirus ORF6结合Rae1-Nup98复合物，这是核孔复合物细胞质表面的一个组成部分，并已被证明可以抑制干扰素反应。在这里，作者提供了Rae1-Nup98与SARS-CoV-2和SARS-CoV ORF6的c端尾部复合物的结构，并提供了ORF6介导的mRNA和STAT1核质转运的阻断的见解。
The emergence of heavily mutated SARS-CoV-2 variants of concern (VOCs) place the international community on high alert. In addition to numerous mutations that map in the spike protein of VOCs, expression of the viral accessory proteins ORF6 and ORF9b also elevate; both are potent interferon antagonists. Here, we present the crystal structures of Rae1-Nup98 in complex with the C-terminal tails (CTT) of SARS-CoV-2 and SARS-CoV ORF6 to 2.85 Å and 2.39 Å resolution, respectively. An invariant methionine (M) 58 residue of ORF6 CTT extends its side chain into a hydrophobic cavity in the Rae1 mRNA binding groove, resembling a bolt-fitting-hole; acidic residues flanking M58 form salt-bridges with Rae1. Our mutagenesis studies identify key residues of ORF6 important for its interaction with Rae1-Nup98 in vitro and in cells, of which M58 is irreplaceable. Furthermore, we show that ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport correlate with the binding affinity between ORF6 and Rae1-Nup98. Finally, binding of ORF6 to Rae1-Nup98 is linked to ORF6-induced interferon antagonism. Taken together, this study reveals the molecular basis for the antagonistic function of Sarbecovirus ORF6, and implies a strategy of using ORF6 CTT-derived peptides for immunosuppressive drug development. Sarbecovirus ORF6 binds to the Rae1-Nup98 complex, a component of the cytoplasmic face of the nuclear pore complex, and has been shown to suppress interferon responses. Here, the authors provide structures of Rae1-Nup98 in complex with the C-terminal tails of SARS-CoV-2 and SARS-CoV ORF6 and provide insights into ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport.
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影响因子：
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DOI：
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发表时间：
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期刊：
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DOI：
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发表时间：
2020-12-04
期刊：
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影响因子：
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通讯作者：
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影响因子：
8.8
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