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冠状病毒双膜囊泡孔复合物的分子结构获解析
作者:小柯机器人 发布时间:2024/8/18 16:48:15

香港大学倪涛、袁硕峰课题组合作的最新研究的解析了冠状病毒双膜囊泡(DMV)孔复合物的分子结构。2024年8月14日,国际学术期刊《自然》发表了这一成果。

研究人员揭示了SARS-CoV-2 nsp3-nsp4孔复合体的分子结构,该结构是通过低温电子断层扫描和分离DMV的子图平均法获得。这些结构揭示了nsp3-nsp4孔复合体具有特殊的化学计量和拓扑结构,它由12 个nsp3拷贝和12 个nsp4拷贝组成,呈4个同心堆叠六聚体环状,模拟微型核孔复合体。

跨膜结构域相互交错,在双膜交界处形成较高的局部曲率,将双膜重组与孔形成结合在一起。外结构域以假12折叠对称形式形成广泛接触面,将孔复合体从膜间空间带出。由精氨酸残基组成的带正电荷的中心环协调假定RNA的转位,这对病毒复制至关重要。

该研究为了解DMV孔形成和RNA转位建立了一个框架,为开发新的抗冠状病毒感染策略提供了结构基础。

据悉,冠状病毒在复制过程中会重塑宿主细胞内膜,形成双膜囊泡,以适应病毒RNA的合成和修饰。SARS-CoV-2非结构蛋白3(nsp3)和nsp4是诱导DMV形成和双跨膜孔形成所需的最小病毒单元,对新合成的病毒RNA运输至关重要。然而,DMV孔复合体的形成机制仍不清楚。

附:英文原文

Title: Molecular architecture of coronavirus double-membrane vesicle pore complex

Author: Huang, Yixin, Wang, Tongyun, Zhong, Lijie, Zhang, Wenxin, Zhang, Yu, Yu, Xiulian, Yuan, Shuofeng, Ni, Tao

Issue&Volume: 2024-08-14

Abstract: Coronaviruses remodel the intracellular host membranes during replication, forming double-membrane vesicles (DMVs) to accommodate viral RNA synthesis and modifications1,2. SARS-CoV-2 non-structural protein 3 (nsp3) and nsp4 are the minimal viral components required to induce DMV formation and to form a double-membrane-spanning pore, essential for the transport of newly synthesized viral RNAs3,4,5. The mechanism of DMV pore complex formation remains unknown. Here we describe the molecular architecture of the SARS-CoV-2 nsp3–nsp4 pore complex, as resolved by cryogenic electron tomography and subtomogram averaging in isolated DMVs. The structures uncover an unexpected stoichiometry and topology of the nsp3–nsp4 pore complex comprising 12 copies each of nsp3 and nsp4, organized in 4 concentric stacking hexamer rings, mimicking a miniature nuclear pore complex. The transmembrane domains are interdigitated to create a high local curvature at the double-membrane junction, coupling double-membrane reorganization with pore formation. The ectodomains form extensive contacts in a pseudo-12-fold symmetry, belting the pore complex from the intermembrane space. A central positively charged ring of arginine residues coordinates the putative RNA translocation, essential for virus replication. Our work establishes a framework for understanding DMV pore formation and RNA translocation, providing a structural basis for the development of new antiviral strategies to combat coronavirus infection.

DOI: 10.1038/s41586-024-07817-y

Source: https://www.nature.com/articles/s41586-024-07817-y

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html