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An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1

Stephanie F. Maurina, John P. O’Sullivan, Geetika Sharma, Daniel C. Pineda Rodriguez, Andrea MacFadden, Francesca Cendali, Morkos A. Henen, Jeffrey S. Kieft, Anum Glasgow, Anna-Lena Steckelberg
doi: https://doi.org/10.1101/2023.06.07.544141
Stephanie F. Maurina
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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John P. O’Sullivan
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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Geetika Sharma
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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Daniel C. Pineda Rodriguez
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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Andrea MacFadden
2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
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Francesca Cendali
2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
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Morkos A. Henen
2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
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Jeffrey S. Kieft
2Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
3RNA BioScience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
4New York Structural Biology Center, New York, NY, USA
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Anum Glasgow
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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Anna-Lena Steckelberg
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
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  • For correspondence: as6282@cumc.columbia.edu
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Abstract

An important pathogenicity factor of SARS-CoV-2 and related coronaviruses is Nsp1, which suppresses host gene expression and stunts antiviral signaling. SARS-CoV-2 Nsp1 binds the ribosome to inhibit translation through mRNA displacement and induces degradation of host mRNAs through an unknown mechanism. Here we show that Nsp1-dependent host shutoff is conserved in diverse coronaviruses, but only Nsp1 from β-CoV inhibits translation through ribosome binding. The C-terminal domain of all β-CoV Nsp1s confers high-affinity ribosome-binding despite low sequence conservation. Modeling of interactions of four Nsp1s to the ribosome identified few absolutely conserved amino acids that, together with an overall conservation in surface charge, form the β-CoV Nsp1 ribosome-binding domain. Contrary to previous models, the Nsp1 ribosome-binding domain is an inefficient translation inhibitor. Instead, the Nsp1-CTD likely functions by recruiting Nsp1’s N-terminal “effector” domain. Finally, we show that a viral cis-acting RNA element has co-evolved to fine-tune SARS-CoV-2 Nsp1 function, but does not provide similar protection against Nsp1 from related viruses. Together, our work provides new insight into the diversity and conservation of ribosome-dependent host-shutoff functions of Nsp1, knowledge that could aide future efforts in pharmacological targeting of Nsp1 from SARS-CoV-2, but also related human-pathogenic β-coronaviruses. Our study also exemplifies how comparing highly divergent Nsp1 variants can help to dissect the different modalities of this multi-functional viral protein.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted June 08, 2023.
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An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1
Stephanie F. Maurina, John P. O’Sullivan, Geetika Sharma, Daniel C. Pineda Rodriguez, Andrea MacFadden, Francesca Cendali, Morkos A. Henen, Jeffrey S. Kieft, Anum Glasgow, Anna-Lena Steckelberg
bioRxiv 2023.06.07.544141; doi: https://doi.org/10.1101/2023.06.07.544141
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An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1
Stephanie F. Maurina, John P. O’Sullivan, Geetika Sharma, Daniel C. Pineda Rodriguez, Andrea MacFadden, Francesca Cendali, Morkos A. Henen, Jeffrey S. Kieft, Anum Glasgow, Anna-Lena Steckelberg
bioRxiv 2023.06.07.544141; doi: https://doi.org/10.1101/2023.06.07.544141

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