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多种新冠病毒变异株的病毒粒子形态及病毒表面刺突蛋白结构

Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants.

作者信息

Ke Zunlong, Peacock Thomas P, Brown Jonathan C, Sheppard Carol M, Croll Tristan I, Kotecha Abhay, Goldhill Daniel H, Barclay Wendy S, Briggs John A G

机构信息

Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany.

Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

出版信息

EMBO J. 2024 Dec;43(24):6469-6495. doi: 10.1038/s44318-024-00303-1. Epub 2024 Nov 14.

DOI:10.1038/s44318-024-00303-1
PMID:39543395
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11649927/
Abstract

The evolution of SARS-CoV-2 variants with increased fitness has been accompanied by structural changes in the spike (S) proteins, which are the major target for the adaptive immune response. Single-particle cryo-EM analysis of soluble S protein from SARS-CoV-2 variants has revealed this structural adaptation at high resolution. The analysis of S trimers in situ on intact virions has the potential to provide more functionally relevant insights into S structure and virion morphology. Here, we characterized B.1, Alpha, Beta, Gamma, Delta, Kappa, and Mu variants by cryo-electron microscopy and tomography, assessing S cleavage, virion morphology, S incorporation, "in-situ" high-resolution S structures, and the range of S conformational states. We found no evidence for adaptive changes in virion morphology, but describe multiple different positions in the S protein where amino acid changes alter local protein structure. Taken together, our data are consistent with a model where amino acid changes at multiple positions from the top to the base of the spike cause structural changes that can modulate the conformational dynamics of the S protein.

摘要

适应性增强的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的进化伴随着刺突（S）蛋白的结构变化，而S蛋白是适应性免疫反应的主要靶点。对SARS-CoV-2变体可溶性S蛋白进行的单颗粒冷冻电镜分析已在高分辨率下揭示了这种结构适应性。对完整病毒粒子上的S三聚体进行原位分析，有可能为S结构和病毒粒子形态提供更多与功能相关的见解。在这里，我们通过冷冻电子显微镜和断层扫描对B.1、阿尔法、贝塔、伽马、德尔塔、卡帕和缪变体进行了表征，评估了S蛋白裂解、病毒粒子形态、S蛋白掺入、“原位”高分辨率S结构以及S构象状态范围。我们没有发现病毒粒子形态发生适应性变化的证据，但描述了S蛋白中多个不同位置，氨基酸变化会改变局部蛋白质结构。综上所述，我们的数据与一个模型一致，即从刺突顶部到底部多个位置的氨基酸变化会导致结构变化，从而调节S蛋白的构象动力学。

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