Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.
Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.
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DOI：
10.15252/embr.202154322
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发表时间：
2022-10-06
期刊：
影响因子：
7.7
通讯作者：
Grove J
中科院分区：
文献类型：
--
作者：
Cantoni D;Murray MJ;Kalemera MD;Dicken SJ;Stejskal L;Brown G;Lytras S;Coey JD;McKenna J;Bridgett S;Simpson D;Fairley D;Thorne LG;Reuschl AK;Forrest C;Ganeshalingham M;Muir L;Palor M;Jarvis L;Willett B;Power UF;McCoy LE;Jolly C;Towers GJ;Doores KJ;Robertson DL;Shepherd AJ;Reeves MB;Bamford CGG;Grove J
SARS - CoV - 2变体的出现加剧了COVID - 19全球卫生危机。到目前为止，所有变异都携带刺突糖蛋白突变，刺突糖蛋白是病毒传播的关键决定因素，负责附着、受体结合和膜融合，也是免疫的重要靶点。突变体经常在尖峰的N端结构域（NTD）承受柔性环的截断；这些修改的功能重要性仍然没有得到很好的描述。我们证明了NTD缺失对于α和欧米克隆变异的有效进入是重要的，并且这与刺突稳定性有关。系统发育分析揭示了sarbecovirus中广泛的NTD环长度多态性，为环重构设定了进化先例。在这些分析的指导下，我们证明仅NTD环长度的变化就足以调节病毒的进入。我们提出NTD环路长度的变化对微调尖峰起作用；这可能为SARS - CoV - 2导航复杂的选择景观提供了一种机制，包括基本功能的优化、免疫驱动的抗原变异和对新宿主的持续适应。SARS - CoV - 2突刺N端结构域的功能重要性尚不清楚。该研究表明，NTD内柔性环的长度变化可以调节刺突活性，以优化SARS - CoV - 2的进入。
The emergence of SARS‐CoV‐2 variants has exacerbated the COVID‐19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N‐terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine‐tune spike; this may provide a mechanism for SARS‐CoV‐2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune‐driven antigenic variation and ongoing adaptation to a new host. The functional importance of the SARS‐CoV‐2 spike N‐terminal domain is poorly understood. This study demonstrates that length variation in flexible loops within the NTD can modulate spike activity to optimise SARS‐CoV‐2 entry.
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DOI：
10.1126/science.abg3055
发表时间：
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期刊：
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影响因子：
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影响因子：
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10.3390/v14020325
发表时间：
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期刊：
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影响因子：
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影响因子：
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