The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85β subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85β, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85β. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85β in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously.

中文翻译：

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1918年甲型流感病毒NS1与PI3K和CRK之间三元相互作用的分子基础。

1918年的甲型流感病毒（IAV）造成了人类历史上最严重的流感大流行。非结构蛋白1（NS1）是1918 IAV的重要毒力因子，可拮抗宿主抗病毒免疫应答。NS1通过与PI3K的p85β亚基结合来激活磷酸肌醇3-激酶（PI3K），从而提高毒性。有趣的是，与其他人类IAV株的NS1不同，1918 NS1劫持了另一种宿主蛋白​​CRK，与p85β形成三元复合物，导致PI3K过度活化。但是，1918 NS1，CRK和PI3K之间三元相互作用的分子基础仍然难以捉摸。在这里，我们报告三元相互作用的结构和热力学基础。我们发现1918 NS1的C末端尾巴（CTT）在与p85β形成的复合物中仍具有高度的柔性。从而，与PI3K配合使用的1918 NS1的CTT可以有效劫持CRK。值得注意的是，我们的研究表明1918 NS1在CRK存在下增强了其对p85β的亲和力，这可能导致PI3K的激活增强。我们的结果提供了有关1918 NS1如何同时劫持两种宿主蛋白​​的结构性见解。