Structural basis for the interaction of SARS‐CoV‐2 virulence factor nsp1 with DNA polymerase α–primase

The molecular mechanisms that drive the infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)—the causative agent of coronavirus disease 2019 (COVID‐19)—are under intense current scrutiny to understand how the virus operates and to uncover ways in which the disease can be pre...

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Bibliographic Details
Published in:	Protein science Vol. 31; no. 2; pp. 333 - 344
Main Authors:	Kilkenny, Mairi L., Veale, Charlotte E., Guppy, Amir, Hardwick, Steven W., Chirgadze, Dimitri Y., Rzechorzek, Neil J., Maman, Joseph D., Pellegrini, Luca
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-02-2022 Wiley Subscription Services, Inc
Subjects:	Coronaviruses COVID-19 Cryoelectron Microscopy cryo‐EM Deoxyribonucleic acid DNA DNA biosynthesis DNA polymerase DNA Polymerase I DNA polymerase α–primase DNA Primase DNA-directed DNA polymerase Electron microscopy Full‐Length Paper Full‐Length Papers Humans Immune response Infections Molecular modelling nsp1 Primase Proteins protein–protein interaction Proteomics Respiratory diseases SARS-CoV-2 Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Viral diseases Viral infections Viral Nonstructural Proteins - genetics Virulence Virulence Factors Viruses SARS-CoV-2 protein-protein interaction nsp1 cryo-EM DNA polymerase α-primase
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Summary:	The molecular mechanisms that drive the infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)—the causative agent of coronavirus disease 2019 (COVID‐19)—are under intense current scrutiny to understand how the virus operates and to uncover ways in which the disease can be prevented or alleviated. Recent proteomic screens of the interactions between viral and host proteins have identified the human proteins targeted by SARS‐CoV‐2. The DNA polymerase α (Pol α)–primase complex or primosome—responsible for initiating DNA synthesis during genomic duplication—was identified as a target of nonstructural protein 1 (nsp1), a major virulence factor in the SARS‐CoV‐2 infection. Here, we validate the published reports of the interaction of nsp1 with the primosome by demonstrating direct binding with purified recombinant components and providing a biochemical characterization of their interaction. Furthermore, we provide a structural basis for the interaction by elucidating the cryo‐electron microscopy structure of nsp1 bound to the primosome. Our findings provide biochemical evidence for the reported targeting of Pol α by the virulence factor nsp1 and suggest that SARS‐CoV‐2 interferes with Pol α's putative role in the immune response during the viral infection. PDB Code(s): 7OPL; EMDB codes: 13020, 13021
Bibliography:	Funding information Wellcome Trust, Grant/Award Number: 104641/Z/14/Z ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Funding information Wellcome Trust, Grant/Award Number: 104641/Z/14/Z
ISSN:	0961-8368 1469-896X
DOI:	10.1002/pro.4220