Molecular architecture of coronavirus double-membrane vesicle pore complex

Yixin Huang, Tongyun Wang, Lijie Zhong, Wenxin Zhang, Yu Zhang, Xiulian Yu, Shuofeng Yuan () and Tao Ni ()
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Yixin Huang: The University of Hong Kong
Tongyun Wang: The University of Hong Kong
Lijie Zhong: The University of Hong Kong
Wenxin Zhang: The University of Hong Kong
Yu Zhang: The University of Hong Kong
Xiulian Yu: The Hong Kong Polytechnic University, Hung Hom
Shuofeng Yuan: The University of Hong Kong
Tao Ni: The University of Hong Kong

Nature, 2024, vol. 633, issue 8028, 224-231

Abstract: 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 RNAs3–5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07817-y

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