Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport

Xiaopan Gao, Huabin Tian, Kaixiang Zhu, Qing Li, Wei Hao, Linyue Wang, Bo Qin, Hongyu Deng () and Sheng Cui ()
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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
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
Sheng Cui: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32489-5

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