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疱疹病毒中膜融合激活的变构机制。

Allosteric mechanism of membrane fusion activation in a herpesvirus.

作者信息

González-Del Pino Gonzalo L, Walsh Richard M, Atanasiu Doina, Cairns Tina M, Saw Wan Ting, Cohen Gary H, Heldwein Ekaterina E

机构信息

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 0211.

Tufts NIH-IRACDA program, Tufts University School of Medicine, Boston, MA 02111.

出版信息

bioRxiv. 2024 Sep 21:2024.09.20.610514. doi: 10.1101/2024.09.20.610514.

DOI:10.1101/2024.09.20.610514
PMID:39345478
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11430019/
Abstract

infect nearly all humans for life, causing diseases that range from painful to life-threatening. These viruses penetrate cells by employing a complex apparatus composed of separate receptor-binding, signal-transmitting, and membrane-fusing components. But how these components coordinate their functions is unknown. Here, we determined the 4.19-angstrom cryoEM reconstruction of the central signal-transmitting component from herpes simplex virus 2, the gH/gL complex, in its elusive pre-activation state. Analysis of the continuum of conformational ensembles observed in cryoEM data revealed a series of structural rearrangements in gH/gL that allosterically transmit the fusion-triggering signal from the receptor-binding glycoprotein gD to the membrane fusogen gB. Furthermore, we identified a structural "switch" element in gH/gL that refolds and flips 180 degrees during the transition from pre-activation to activated form. Conservation of this "switch" in gH/gL homologs suggests that the proposed fusion triggering mechanism may apply to all and points to a new target for subunit-based vaccines and treatment efforts.

摘要

几乎感染所有人类并伴随终生，引发从疼痛到危及生命等一系列疾病。这些病毒通过利用一种由单独的受体结合、信号传递和膜融合成分组成的复杂机制穿透细胞。但这些成分如何协调其功能尚不清楚。在此，我们确定了单纯疱疹病毒2的核心信号传递成分gH/gL复合物处于难以捉摸的预激活状态下的4.19埃冷冻电镜重建结构。对冷冻电镜数据中观察到的构象集合连续体的分析揭示了gH/gL中的一系列结构重排，这些重排将融合触发信号从受体结合糖蛋白gD变构传递至膜融合蛋白gB。此外，我们在gH/gL中鉴定出一个结构“开关”元件，该元件在从预激活形式转变为激活形式的过程中会重新折叠并翻转180度。gH/gL同源物中这种“开关”的保守性表明，所提出的融合触发机制可能适用于所有此类病毒，并为基于亚单位的疫苗和治疗努力指明了一个新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/aaf7794e0c6c/nihpp-2024.09.20.610514v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/17fd5c2494fd/nihpp-2024.09.20.610514v1-f0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/4c6b8fb29164/nihpp-2024.09.20.610514v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/3c4992575821/nihpp-2024.09.20.610514v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/0630c7ea24f7/nihpp-2024.09.20.610514v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/d89a0ba58e7b/nihpp-2024.09.20.610514v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/d807a25f1fad/nihpp-2024.09.20.610514v1-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/e30c9f032428/nihpp-2024.09.20.610514v1-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/0e243dc41f7a/nihpp-2024.09.20.610514v1-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/ccc16467c35d/nihpp-2024.09.20.610514v1-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/fc8cc5f0fd93/nihpp-2024.09.20.610514v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/ba13b4552688/nihpp-2024.09.20.610514v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/5f0db4c1e25c/nihpp-2024.09.20.610514v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/aaf7794e0c6c/nihpp-2024.09.20.610514v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/17fd5c2494fd/nihpp-2024.09.20.610514v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/780c0b9cb5ac/nihpp-2024.09.20.610514v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/4c6b8fb29164/nihpp-2024.09.20.610514v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/3c4992575821/nihpp-2024.09.20.610514v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/0630c7ea24f7/nihpp-2024.09.20.610514v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/d89a0ba58e7b/nihpp-2024.09.20.610514v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/d807a25f1fad/nihpp-2024.09.20.610514v1-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/e30c9f032428/nihpp-2024.09.20.610514v1-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/0e243dc41f7a/nihpp-2024.09.20.610514v1-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/ccc16467c35d/nihpp-2024.09.20.610514v1-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/fc8cc5f0fd93/nihpp-2024.09.20.610514v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/ba13b4552688/nihpp-2024.09.20.610514v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/5f0db4c1e25c/nihpp-2024.09.20.610514v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83ce/11430019/aaf7794e0c6c/nihpp-2024.09.20.610514v1-f0004.jpg

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本文引用的文献

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Annu Rev Virol. 2023 Sep 29;10(1):139-161. doi: 10.1146/annurev-virology-111821-093413.
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3DFlex: determining structure and motion of flexible proteins from cryo-EM.3DFlex：从冷冻电镜中确定柔性蛋白的结构和运动。
Nat Methods. 2023 Jun;20(6):860-870. doi: 10.1038/s41592-023-01853-8. Epub 2023 May 11.
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Herpes Simplex Virus 1 Entry Glycoproteins Form Complexes before and during Membrane Fusion.单纯疱疹病毒 1 进入糖蛋白在膜融合前后形成复合物。
mBio. 2022 Oct 26;13(5):e0203922. doi: 10.1128/mbio.02039-22. Epub 2022 Aug 16.
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A surface pocket in the cytoplasmic domain of the herpes simplex virus fusogen gB controls membrane fusion.单纯疱疹病毒融合糖蛋白 gB 胞质域中的表面口袋控制膜融合。
PLoS Pathog. 2022 Jun 29;18(6):e1010435. doi: 10.1371/journal.ppat.1010435. eCollection 2022 Jun.
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Well Put Together-A Guide to Accessorizing with the Herpesvirus gH/gL Complexes.《搭配疱疹病毒 gH/gL 复合物的指南》
Viruses. 2022 Jan 30;14(2):296. doi: 10.3390/v14020296.
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3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM.3D 变异性分析：从单颗粒冷冻电镜中解析连续的柔韧性和离散的异质性。
J Struct Biol. 2021 Jun;213(2):107702. doi: 10.1016/j.jsb.2021.107702. Epub 2021 Feb 11.
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CryoDRGN: reconstruction of heterogeneous cryo-EM structures using neural networks.CryoDRGN：使用神经网络重建异质冷冻电镜结构。
Nat Methods. 2021 Feb;18(2):176-185. doi: 10.1038/s41592-020-01049-4. Epub 2021 Feb 4.
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Using Split Luciferase Assay and anti-HSV Glycoprotein Monoclonal Antibodies to Predict a Functional Binding Site Between gD and gH/gL.使用分裂荧光素酶测定法和抗单纯疱疹病毒糖蛋白单克隆抗体预测gD与gH/gL之间的功能性结合位点。
J Virol. 2021 Mar 25;95(8). doi: 10.1128/JVI.00053-21. Epub 2021 Jan 27.
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The structural basis of herpesvirus entry.疱疹病毒进入的结构基础。
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Entry of Alphaherpesviruses.α疱疹病毒的进入。
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