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

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Kilkenny ML, Veale CE, Guppy A, Hardwick SW, Chirgadze DY, Rzechorzek NJ, Maman JD, Pellegrini L
OpenAccess logo Protein Sci 31 333-344 (2022)
Cited: 17 times
EuropePMC logo PMID: 34719824

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.

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  1. Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2. Gao K, Wang R, Chen J, Cheng L, Frishcosy J, Huzumi Y, Qiu Y, Schluckbier T, Wei X, Wei GW. Chem Rev 122 11287-11368 (2022)
  2. CST-Polα/Primase: the second telomere maintenance machine. Cai SW, de Lange T. Genes Dev 37 555-569 (2023)
  3. Coronaviral Infection and Interferon Response: The Virus-Host Arms Race and COVID-19. Liu Q, Chi S, Dmytruk K, Dmytruk O, Tan S. Viruses 14 1349 (2022)
  4. Models for human telomere C-strand fill-in by CST-Polα-primase. He Q, Lim CJ. Trends Biochem Sci 48 860-872 (2023)
  5. Coronavirus takeover of host cell translation and intracellular antiviral response: a molecular perspective. Karousis ED, Schubert K, Ban N. EMBO J 43 151-167 (2024)

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  1. Cryo-EM structure of the human CST-Polα/primase complex in a recruitment state. Cai SW, Zinder JC, Svetlov V, Bush MW, Nudler E, Walz T, de Lange T. Nat Struct Mol Biol 29 813-819 (2022)
  2. Structure of Tetrahymena telomerase-bound CST with polymerase α-primase. He Y, Song H, Chan H, Liu B, Wang Y, Sušac L, Zhou ZH, Feigon J. Nature 608 813-818 (2022)
  3. Structural basis for the interaction of SARS-CoV-2 virulence factor nsp1 with DNA polymerase α-primase. Kilkenny ML, Veale CE, Guppy A, Hardwick SW, Chirgadze DY, Rzechorzek NJ, Maman JD, Pellegrini L. Protein Sci 31 333-344 (2022)
  4. Insight into RNA-DNA primer length counting by human primosome. Baranovskiy AG, Lisova AE, Morstadt LM, Babayeva ND, Tahirov TH. Nucleic Acids Res 50 6264-6270 (2022)
  5. Structures of human primosome elongation complexes. He Q, Baranovskiy AG, Morstadt LM, Lisova AE, Babayeva ND, Lusk BL, Lim CJ, Tahirov TH. Nat Struct Mol Biol 30 579-583 (2023)
  6. Two Ligand-Binding Sites on SARS-CoV-2 Non-Structural Protein 1 Revealed by Fragment-Based X-ray Screening. Ma S, Damfo S, Lou J, Pinotsis N, Bowler MW, Haider S, Kozielski F. Int J Mol Sci 23 12448 (2022)
  7. Atlas of interactions between SARS-CoV-2 macromolecules and host proteins. Li G, Tang Z, Fan W, Wang X, Huang L, Jia Y, Wang M, Hu Z, Zhou Y. Cell Insight 2 100068 (2023)
  8. A mechanistic model of primer synthesis from catalytic structures of DNA polymerase α-primase. Mullins EA, Salay LE, Durie CL, Bradley NP, Jackman JE, Ohi MD, Chazin WJ, Eichman BF. Nat Struct Mol Biol 31 777-790 (2024)
  9. Inhibition of mRNA nuclear export promotes SARS-CoV-2 pathogenesis. Mei M, Cupic A, Miorin L, Ye C, Cagatay T, Zhang K, Patel K, Wilson N, McDonald WH, Crossland NA, Lo M, Rutkowska M, Aslam S, Mena I, Martinez-Sobrido L, Ren Y, García-Sastre A, Fontoura BMA. Proc Natl Acad Sci U S A 121 e2314166121 (2024)
  10. SARS-CoV2 Nsp1 is a metal-dependent DNA and RNA endonuclease. Salgueiro BA, Saramago M, Tully MD, Issoglio F, Silva STN, Paiva ACF, Arraiano CM, Matias PM, Matos RG, Moe E, Romão CV. Biometals (2024)


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