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静电导向的构象选择机制促进了 SARS-CoV-2 刺突蛋白的变异。

An Electrostatically-steered Conformational Selection Mechanism Promotes SARS-CoV-2 Spike Protein Variation.

机构信息

Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany; RGCC International GmbH, Baarerstrasse 95, Zug 6300, Switzerland; BioSolutions GmbH, Weinbergweg 22, 06120 Halle/Saale, Germany.

Interdisciplinary Research Center HALOmem, Charles Tanford Protein Center, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3a, 06120 Halle/Saale, Germany.

出版信息

J Mol Biol. 2022 Jul 15;434(13):167637. doi: 10.1016/j.jmb.2022.167637. Epub 2022 May 17.

DOI:10.1016/j.jmb.2022.167637
PMID:35595165
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9112565/
Abstract

After two years since the outbreak, the COVID-19 pandemic remains a global public health emergency. SARS-CoV-2 variants with substitutions on the spike (S) protein emerge increasing the risk of immune evasion and cross-species transmission. Here, we analyzed the evolution of the S protein as recorded in 276,712 samples collected before the start of vaccination efforts. Our analysis shows that most variants destabilize the S protein trimer, increase its conformational heterogeneity and improve the odds of the recognition by the host cell receptor. Most frequent substitutions promote overall hydrophobicity by replacing charged amino acids, reducing stabilizing local interactions in the unbound S protein trimer. Moreover, our results identify "forbidden" regions that rarely show any sequence variation, and which are related to conformational changes occurring upon fusion. These results are significant for understanding the structure and function of SARS-CoV-2 related proteins which is a critical step in vaccine development and epidemiological surveillance.

摘要

自疫情爆发以来已经过去了两年，COVID-19 大流行仍然是全球公共卫生紧急事件。在刺突（S）蛋白上发生取代的 SARS-CoV-2 变体增加了免疫逃逸和跨物种传播的风险。在这里，我们分析了在疫苗接种工作开始之前收集的 276712 个样本中记录的 S 蛋白的进化。我们的分析表明，大多数变体使 S 蛋白三聚体不稳定，增加其构象异质性，并提高被宿主细胞受体识别的几率。最常见的取代通过取代带电氨基酸来增加整体疏水性，减少未结合的 S 蛋白三聚体中稳定的局部相互作用。此外，我们的结果确定了很少出现任何序列变异的“禁止”区域，这些区域与融合时发生的构象变化有关。这些结果对于理解 SARS-CoV-2 相关蛋白的结构和功能具有重要意义，这是疫苗开发和流行病学监测的关键步骤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/194b8bd7b854/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/7073cdd3822c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/2e2530d722ce/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/c61a4359993f/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/2b10f3076e3f/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/a8fd675a7558/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/f0e3e974d2f2/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/e8bc2051ef3b/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/35a4819f066a/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/b699cc6636a9/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/a1e78b77290c/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/194b8bd7b854/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/7073cdd3822c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/2e2530d722ce/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/c61a4359993f/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/2b10f3076e3f/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/a8fd675a7558/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/f0e3e974d2f2/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/e8bc2051ef3b/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/35a4819f066a/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/b699cc6636a9/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/a1e78b77290c/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f121/9112565/194b8bd7b854/gr10_lrg.jpg

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