N-terminal domain mutations of the spike protein are structurally implicated in epitope recognition in emerging SARS-CoV-2 strains.
N-terminal domain mutations of the spike protein are structurally implicated in epitope recognition in emerging SARS-CoV-2 strains.
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DOI：
10.1016/j.csbj.2021.10.004
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发表时间：
2021
影响因子：
6
通讯作者：
Rampias T
中科院分区：
文献类型：
--
作者：
Klinakis A;Cournia Z;Rampias T
在过去两年中，世界遭受了由严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）引起的全球大流行的蹂躏。SARS-CoV-2基因组中影响病毒传染性和/或免疫原性的获得性突变导致了许多与原武汉毒株相比具有更高传播性的新毒株。在这种情况下，SARS-CoV-2刺突蛋白受体结合域（RBD）的突变已被广泛研究。然而，位于RBD附近的n端结构域（NTD）内的突变和缺失研究较少。其中许多是在某些β薄片连接环中发现的，与SARS-CoV和其他相关的β冠状病毒相比，SARS-CoV-2中的β薄片连接环出奇地长。在这里，我们对这些环内携带突变和缺失的新菌株进行了结构和流行病学研究。我们发现了短期和长距离的相互作用，这些相互作用稳定了NTD环，并形成了一个关键的表位，这对于来自恢复期血浆的各种中和抗体的识别至关重要。在这些环中发现的不同突变/缺失中，在不同的快速传播菌株中发现了Ala 67和Asp 80突变以及His 69/Val 70和Tyr 144缺失。同样，在具有高传播率的菌株中，发现241-243和246-252氨基酸的缺失会影响NTD环的网络。我们的结构发现提供了关于这些突变/缺失在改变表位结构中的作用，从而影响刺突蛋白NTD区域的免疫反应性。
During the past two years, the world has been ravaged by a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acquired mutations in the SARS-CoV-2 genome affecting virus infectivity and/or immunogenicity have led to a number of novel strains with higher transmissibility compared to the original Wuhan strain. Mutations in the receptor binding domain (RBD) of the SARS-CoV-2 spike protein have been extensively studied in this context. However, mutations and deletions within the N-terminal domain (NTD) located adjacent to the RBD are less studied. Many of these are found within certain β sheet-linking loops, which are surprisingly long in SARS-CoV-2 in comparison to SARS-CoV and other related β coronaviruses. Here, we perform a structural and epidemiological study of novel strains carrying mutations and deletions within these loops. We identify short and long-distance interactions that stabilize the NTD loops and form a critical epitope that is essential for the recognition by a wide variety of neutralizing antibodies from convalescent plasma. Among the different mutations/deletions found in these loops, Ala 67 and Asp 80 mutations as well as His 69/Val 70 and Tyr 144 deletions have been identified in different fast-spreading strains. Similarly, deletions in amino acids 241–243 and 246–252 have been found to affect the network of NTD loops in strains with high transmissibility. Our structural findings provide insight regarding the role of these mutations/deletions in altering the epitope structure and thus affecting the immunoreactivity of the NTD region of spike protein.
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