A Trimeric Hydrophobic Zipper Mediates the Intramembrane Assembly of SARS-CoV-2 Spike
A Trimeric Hydrophobic Zipper Mediates the Intramembrane Assembly of SARS-CoV-2 Spike
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DOI：
10.1021/jacs.1c02394
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发表时间：
2021-06-04
影响因子：
15
通讯作者：
Chou, James J.
中科院分区：
文献类型：
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作者：
Fu, Qingshan;Chou, James J.
SARS-CoV-2的S蛋白是介导膜融合和病毒进入的I型膜蛋白。大量的结构信息可用于S的胞外域，宿主免疫系统的主要靶点，但关于其跨膜结构域（TMD）及其膜近端区域知之甚少。在这里，我们确定了NMR结构的S蛋白TMD的双胞，密切模仿脂质双层。TMD结构是在膜中自发组装的跨膜α-螺旋（TMH）三聚体。三聚体结构显示出沿3倍轴沿着的广泛疏水核心，其类似于三聚体亮氨酸/异亮氨酸拉链，但具有四聚体而不是七聚体重复。三聚体的核心是强大的bicelles，抵抗氢氘交换数周。尽管高度稳定，但结构引导诱变鉴定出可完全解离TMD三聚体的单一突变。多项研究表明，病毒融合蛋白的膜锚可以形成高度特异性的寡聚体，但这些寡聚体的确切功能尚不清楚。我们的发现应该指导未来的实验来解决SARS冠状病毒的上述问题。
The S protein of SARS-CoV-2 is a type I membrane protein that mediates membrane fusion and viral entry. A vast amount of structural information is available for the ectodomain of S, a primary target by the host immune system, but much less is known regarding its transmembrane domain (TMD) and its membrane-proximal regions. Here, we determined the NMR structure of the S protein TMD in bicelles that closely mimic a lipid bilayer. The TMD structure is a transmembrane alpha-helix (TMH) trimer that assembles spontaneously in a membrane. The trimer structure shows an extensive hydrophobic core along the 3-fold axis that resembles that of a trimeric leucine/isoleucine zipper, but with tetrad, not heptad, repeats. The trimeric core is strong in bicelles, resisting hydrogen-deuterium exchange for weeks. Although highly stable, structural guided mutagenesis identified single mutations that can completely dissociate the TMD trimer. Multiple studies have shown that the membrane anchors of viral fusion proteins can form highly specific oligomers, but the exact function of these oligomers remains unclear. Our findings should guide future experiments to address the above question for SARS coronaviruses.