hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics.
hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics.
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DOI：
10.1021/acsinfecdis.3c00010
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发表时间：
2023-06-09
影响因子：
5.3
通讯作者：
Lee, Kelly K. K.
中科院分区：
文献类型：
--
作者：
Chen, Chengbo;Zhu, Richard;Hodge, Edgar A.;Diaz-Salinas, Marco A.;Nguyen, Adam;Munro, James B.;Lee, Kelly K. K.
当刺突糖蛋白 (S) 与人类 ACE2 (hACE2) 受体对接时，SARS-CoV 和 SARS-CoV-2 就开始进入细胞。虽然这两种冠状病毒具有共同的 S 受体和结构，但它们在与 hACE2 的相互作用以及触发融合机的 S 蛋白水解加工方面表现出差异。了解这些差异如何影响 S 激活是了解其功能和病毒发病机制的关键。在这里，我们使用氢/氘交换质谱 (HDX-MS) 研究了 SARS-CoV 和 SARS-CoV-2 S 中 hACE2 诱导的激活。 HDX-MS 揭示了未结合 S 的动力学差异，包括开放/闭合构象转换和 D614G 诱导的 S 稳定性。 hACE2 结合后，观察到变构变化转导的显着差异，从受体结合域延伸到蛋白水解裂解位点和融合肽附近的区域。此外，我们报告说，与饱和单体 hACE2 结合相比，二聚体 hACE2（受体的天然寡聚形式）不会在 S 中产生任何更明显的结构效应。这些实验为受体诱导的 Sarbecovirus 刺突蛋白激活提供了机制见解。
SARS-CoV and SARS-CoV-2 cell entry begins when spike glycoprotein (S) docks with the human ACE2 (hACE2) receptor. While the two coronaviruses share a common receptor and architecture of S, they exhibit differences in interactions with hACE2 as well as differences in proteolytic processing of S that trigger the fusion machine. Understanding how those differences impact S activation is key to understand its function and viral pathogenesis. Here, we investigate hACE2-induced activation in SARS-CoV and SARS-CoV-2 S using hydrogen/deuterium-exchange mass spectrometry (HDX-MS). HDX-MS revealed differences in dynamics in unbound S, including open/closed conformational switching and D614G-induced S stability. Upon hACE2 binding, notable differences in transduction of allosteric changes were observed extending from the receptor binding domain to regions proximal to proteolytic cleavage sites and the fusion peptide. Furthermore, we report that dimeric hACE2, the native oligomeric form of the receptor, does not lead to any more pronounced structural effect in S compared to saturated monomeric hACE2 binding. These experiments provide mechanistic insights into receptor-induced activation of Sarbecovirus spike proteins.
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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