An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.
An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.
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DOI：
10.1016/j.celrep.2015.03.034
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发表时间：
2015-04-21
期刊：
影响因子：
8.8
通讯作者：
Amarasinghe GK
中科院分区：
文献类型：
--
作者：
Leung DW;Borek D;Luthra P;Binning JM;Anantpadma M;Liu G;Harvey IB;Su Z;Endlich-Frazier A;Pan J;Shabman RS;Chiu W;Davey RA;Otwinowski Z;Basler CF;Amarasinghe GK
在病毒 RNA 合成过程中，埃博拉病毒 (EBOV) 核蛋白 (NP) 在 RNA 模板结合形式和无模板形式之间交替，为病毒聚合酶提供接近 RNA 模板的途径。此外，必须防止新合成的 NP 不加区别地与非同源 RNA 结合。在这里，我们研究这些关键过程的分子基础。我们鉴定了一种源自 EBOV VP35 (NPBP) 的内在无序肽，它以高亲和力和特异性结合 NP，抑制 NP 寡聚化，并在体外从 NP-RNA 复合物中释放 RNA。 NPBP/ΔNPNTD 复合物的结构以 3.7 Å 分辨率解析，揭示了 NPBP 肽如何封闭大表面积，这对于 NP-NP 和 NP-RNA 相互作用以及病毒 RNA 合成非常重要。总之，我们的结果确定了一个高度保守的病毒界面，该界面对于埃博拉病毒复制很重要，并且可以作为治疗开发的目标。
During viral RNA synthesis, Ebola virus (EBOV) nucleoprotein (NP) alternates between an RNA template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP) that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes in vitro. The structure of the NPBP/ΔNPNTD complex, solved to 3.7 Å resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development.