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Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport

Author

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  • Xiaopan Gao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Huabin Tian

    (Chinese Academy of Sciences)

  • Kaixiang Zhu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qing Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wei Hao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Linyue Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bo Qin

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Hongyu Deng

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Sheng Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Southern University of Science and Technology)

Abstract

The emergence of heavily mutated SARS-CoV-2 variants of concern (VOCs) place the international community on high alert. In addition to numerous mutations that map in the spike protein of VOCs, expression of the viral accessory proteins ORF6 and ORF9b also elevate; both are potent interferon antagonists. Here, we present the crystal structures of Rae1-Nup98 in complex with the C-terminal tails (CTT) of SARS-CoV-2 and SARS-CoV ORF6 to 2.85 Å and 2.39 Å resolution, respectively. An invariant methionine (M) 58 residue of ORF6 CTT extends its side chain into a hydrophobic cavity in the Rae1 mRNA binding groove, resembling a bolt-fitting-hole; acidic residues flanking M58 form salt-bridges with Rae1. Our mutagenesis studies identify key residues of ORF6 important for its interaction with Rae1-Nup98 in vitro and in cells, of which M58 is irreplaceable. Furthermore, we show that ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport correlate with the binding affinity between ORF6 and Rae1-Nup98. Finally, binding of ORF6 to Rae1-Nup98 is linked to ORF6-induced interferon antagonism. Taken together, this study reveals the molecular basis for the antagonistic function of Sarbecovirus ORF6, and implies a strategy of using ORF6 CTT-derived peptides for immunosuppressive drug development.

Suggested Citation

  • Xiaopan Gao & Huabin Tian & Kaixiang Zhu & Qing Li & Wei Hao & Linyue Wang & Bo Qin & Hongyu Deng & Sheng Cui, 2022. "Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32489-5
    DOI: 10.1038/s41467-022-32489-5
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    as
    1. David E. Gordon & Gwendolyn M. Jang & Mehdi Bouhaddou & Jiewei Xu & Kirsten Obernier & Kris M. White & Matthew J. O’Meara & Veronica V. Rezelj & Jeffrey Z. Guo & Danielle L. Swaney & Tia A. Tummino & , 2020. "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing," Nature, Nature, vol. 583(7816), pages 459-468, July.
    2. Xiaopan Gao & Kaixiang Zhu & Bo Qin & Vincent Olieric & Meitian Wang & Sheng Cui, 2021. "Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    3. Nea, 2020. "Case law," Nuclear Law Bulletin, OECD Publishing, vol. 2020(1).
    4. Dami A. Collier & Anna Marco & Isabella A. T. M. Ferreira & Bo Meng & Rawlings P. Datir & Alexandra C. Walls & Steven A. Kemp & Jessica Bassi & Dora Pinto & Chiara Silacci-Fregni & Siro Bianchi & M. A, 2021. "Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies," Nature, Nature, vol. 593(7857), pages 136-141, May.
    5. Nea, 2020. "Case Law: 0," Nuclear Law Bulletin, OECD Publishing, vol. 2019(1).
    6. Nea, 2020. "Case law: 0," Nuclear Law Bulletin, OECD Publishing, vol. 2019(2).
    7. Xiaobo Lei & Xiaojing Dong & Ruiyi Ma & Wenjing Wang & Xia Xiao & Zhongqin Tian & Conghui Wang & Ying Wang & Li Li & Lili Ren & Fei Guo & Zhendong Zhao & Zhuo Zhou & Zichun Xiang & Jianwei Wang, 2020. "Activation and evasion of type I interferon responses by SARS-CoV-2," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    8. Steven A. Kemp & Dami A. Collier & Rawlings P. Datir & Isabella A. T. M. Ferreira & Salma Gayed & Aminu Jahun & Myra Hosmillo & Chloe Rees-Spear & Petra Mlcochova & Ines Ushiro Lumb & David J. Roberts, 2021. "SARS-CoV-2 evolution during treatment of chronic infection," Nature, Nature, vol. 592(7853), pages 277-282, April.
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