Structural basis for the interaction of SARS-CoV-2 virulence factor nsp1 with DNA polymerase α-primase.
Authors
Kilkenny, Mairi L
Veale, Charlotte E
Guppy, Amir
Hardwick, Steven W
Chirgadze, Dimitri Y
Rzechorzek, Neil J
Maman, Joseph D
Publication Date
2022-02Journal Title
Protein Sci
ISSN
0961-8368
Publisher
Wiley
Language
en
Type
Article
This Version
AO
VoR
Metadata
Show full item recordCitation
Kilkenny, M. L., Veale, C. E., Guppy, A., Hardwick, S. W., Chirgadze, D. Y., Rzechorzek, N. J., Maman, J. D., & et al. (2022). Structural basis for the interaction of SARS-CoV-2 virulence factor nsp1 with DNA polymerase α-primase.. Protein Sci https://doi.org/10.1002/pro.4220
Abstract
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.
Keywords
DNA polymerase α-primase, SARS-CoV-2, cryo-EM, nsp1, protein-protein interaction, COVID-19, Cryoelectron Microscopy, DNA Polymerase I, DNA Primase, Humans, Proteomics, SARS-CoV-2, Viral Nonstructural Proteins, Virulence Factors
Sponsorship
Wellcome Trust (104641/Z/14/Z)
Identifiers
pro4220
External DOI: https://doi.org/10.1002/pro.4220
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330770
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk