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Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

Author

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  • Chris H. Hill

    (Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road
    MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Ave
    University of York, Wentworth Way)

  • Lukas Pekarek

    (Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI))

  • Sawsan Napthine

    (Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road)

  • Anuja Kibe

    (Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI))

  • Andrew E. Firth

    (Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road)

  • Stephen C. Graham

    (Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road)

  • Neva Caliskan

    (Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI)
    Medical Faculty, Julius-Maximilians University Würzburg, Josef-Schneider-Straße 2/D15)

  • Ian Brierley

    (Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road)

Abstract

Programmed –1 ribosomal frameshifting (PRF) in cardioviruses is activated by the 2A protein, a multi-functional virulence factor that also inhibits cap-dependent translational initiation. Here we present the X-ray crystal structure of 2A and show that it selectively binds to a pseudoknot-like conformation of the PRF stimulatory RNA element in the viral genome. Using optical tweezers, we demonstrate that 2A stabilises this RNA element, likely explaining the increase in PRF efficiency in the presence of 2A. Next, we demonstrate a strong interaction between 2A and the small ribosomal subunit and present a cryo-EM structure of 2A bound to initiated 70S ribosomes. Multiple copies of 2A bind to the 16S rRNA where they may compete for binding with initiation and elongation factors. Together, these results define the structural basis for RNA recognition by 2A, show how 2A-mediated stabilisation of an RNA pseudoknot promotes PRF, and reveal how 2A accumulation may shut down translation during virus infection.

Suggested Citation

  • Chris H. Hill & Lukas Pekarek & Sawsan Napthine & Anuja Kibe & Andrew E. Firth & Stephen C. Graham & Neva Caliskan & Ian Brierley, 2021. "Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27400-7
    DOI: 10.1038/s41467-021-27400-7
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    References listed on IDEAS

    as
    1. Sawsan Napthine & Roger Ling & Leanne K. Finch & Joshua D. Jones & Susanne Bell & Ian Brierley & Andrew E. Firth, 2017. "Protein-directed ribosomal frameshifting temporally regulates gene expression," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    2. Anna B. Loveland & Gabriel Demo & Andrei A. Korostelev, 2020. "Cryo-EM of elongating ribosome with EF-Tu•GTP elucidates tRNA proofreading," Nature, Nature, vol. 584(7822), pages 640-645, August.
    3. Jin Chen & Alexey Petrov & Magnus Johansson & Albert Tsai & Seán E. O’Leary & Joseph D. Puglisi, 2014. "Dynamic pathways of −1 translational frameshifting," Nature, Nature, vol. 512(7514), pages 328-332, August.
    4. Lars V. Bock & Neva Caliskan & Natalia Korniy & Frank Peske & Marina V. Rodnina & Helmut Grubmüller, 2019. "Thermodynamic control of −1 programmed ribosomal frameshifting," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    5. Jin-Der Wen & Laura Lancaster & Courtney Hodges & Ana-Carolina Zeri & Shige H. Yoshimura & Harry F. Noller & Carlos Bustamante & Ignacio Tinoco, 2008. "Following translation by single ribosomes one codon at a time," Nature, Nature, vol. 452(7187), pages 598-603, April.
    6. Olivier Namy & Stephen J. Moran & David I. Stuart & Robert J. C. Gilbert & Ian Brierley, 2006. "A mechanical explanation of RNA pseudoknot function in programmed ribosomal frameshifting," Nature, Nature, vol. 441(7090), pages 244-247, May.
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