Molecular Mechanism for LAMP1 Recognition by Lassa Virus
Molecular Mechanism for LAMP1 Recognition by Lassa Virus
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DOI：
10.1128/jvi.00651-15
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发表时间：
2015-08-01
影响因子：
5.4
通讯作者：
Diskin, Ron
中科院分区：
文献类型：
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作者：
Cohen-Dvashi, Hadas;Cohen, Nadav;Diskin, Ron
拉沙病毒是一种臭名昭著的人类病原体，每年在西非感染数千人，导致严重的病毒性出血热和显著的死亡率。拉沙病毒的表面糖蛋白通过其GP1亚基介导受体识别。在这里，我们报告的晶体结构的GP1从拉沙病毒，这是第一个代表GP1结构的旧世界沙粒病毒。我们确定了一个独特的组氨酸三联体，形成了一个结合位点的LAMP 1，一个已知的溶酶体蛋白最近发现是一个重要的受体内化拉沙病毒在酸性pH值。我们证明，这种组氨酸三联体，这是高度保守的旧世界沙粒病毒，突变损害LAMP 1的识别。我们的生化和结构数据进一步表明，GP1从拉沙病毒可能会发生不可逆的构象变化，可以作为免疫诱饵机制。与我们在GP1表面识别的可变区一起，这可能是拉沙病毒利用以避免基于抗体的免疫应答的两种不同机制。重要的是，病毒蛋白质原子分辨率的结构数据是在分子水平上理解其功能的关键，并且可以促进对抗病毒感染的新途径。在这里，我们使用X射线蛋白质晶体学来破译拉沙病毒受体结合结构域（GP1）的晶体结构。这是一种致病病毒，在西非造成严重疾病和死亡。这种结构揭示了被称为旧世界沙粒病毒的病毒组的GP1结构域的整体结构。利用这些结构信息，我们阐明了拉沙病毒与LAMP1结合的pH开关机制，LAMP1是一种最近发现的对成功感染至关重要的宿主受体。最后，我们的结构分析表明，拉沙病毒可能利用两种新的免疫逃避机制来逃避基于抗体的免疫反应。
Lassa virus is a notorious human pathogen that infects many thousands of people each year in West Africa, causing severe viral hemorrhagic fevers and significant mortality. The surface glycoprotein of Lassa virus mediates receptor recognition through its GP1 subunit. Here we report the crystal structure of GP1 from Lassa virus, which is the first representative GP1 structure for Old World arenaviruses. We identify a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein recently discovered to be a critical receptor for internalized Lassa virus at acidic pH. We demonstrate that mutation of this histidine triad, which is highly conserved among Old World arenaviruses, impairs LAMP1 recognition. Our biochemical and structural data further suggest that GP1 from Lassa virus may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Together with a variable region that we identify on the surface of GP1, those could be two distinct mechanisms that Lassa virus utilizes to avoid antibody-based immune response.IMPORTANCEStructural data at atomic resolution for viral proteins is key for understanding their function at the molecular level and can facilitate novel avenues for combating viral infections. Here we used X-ray protein crystallography to decipher the crystal structure of the receptor-binding domain (GP1) from Lassa virus. This is a pathogenic virus that causes significant illness and mortality in West Africa. This structure reveals the overall architecture of GP1 domains from the group of viruses known as the Old World arenaviruses. Using this structural information, we elucidated the mechanisms for pH switch and binding of Lassa virus to LAMP1, a recently identified host receptor that is critical for successful infection. Lastly, our structural analysis suggests two novel immune evasion mechanisms that Lassa virus may utilize to escape antibody-based immune response.