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Cryo electron microscopy of DNA Polymerase alpha - primase bound to SARS-CoV-2 nsp1 virulence factor

ABSTRACT:

SUBMITTER: Luca Pellegrini

PROVIDER: EMPIAR-11477 | biostudies-other |

REPOSITORIES: biostudies-other

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

Kilkenny Mairi L ML Veale Charlotte E CE Guppy Amir A Hardwick Steven W SW Chirgadze Dimitri Y DY Rzechorzek Neil J NJ Maman Joseph D JD Pellegrini Luca L

Protein science : a publication of the Protein Society 20211112 2

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 compl ...[more]

PMID: 34719824

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

Project description: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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The atomic portrait of SARS-CoV-2 as captured by cryo-electron microscopy.

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Cdc6-induced conformational changes in ORC bound to origin DNA revealed by cryo-electron microscopy.

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