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Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression

Author

Listed:
  • Shuting Yan

    (New York University)

  • Qiyao Zhu

    (New York University)

  • Swati Jain

    (New York University)

  • Tamar Schlick

    (New York University
    New York University
    NYU Shanghai
    New York University)

Abstract

The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE experiments, the FSE adopts a heterogeneous, length-dependent conformational landscape consisting of an assumed 3-stem H-type pseudoknot (graph motif 3_6), and two alternative motifs (3_3 and 3_5). Here, for the first time, we build and simulate, by microsecond molecular dynamics, 30 models for all three motifs plus motif-stabilizing mutants at different lengths. Our 3_6 pseudoknot systems, which agree with experimental structures, reveal interconvertible L and linear conformations likely related to ribosomal pausing and frameshifting. The 3_6 mutant inhibits this transformation and could hamper frameshifting. Our 3_3 systems exhibit length-dependent stem interactions that point to a potential transition pathway connecting the three motifs during ribosomal elongation. Together, our observations provide new insights into frameshifting mechanisms and anti-viral strategies.

Suggested Citation

  • Shuting Yan & Qiyao Zhu & Swati Jain & Tamar Schlick, 2022. "Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31353-w
    DOI: 10.1038/s41467-022-31353-w
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    1. Krishna Neupane & Meng Zhao & Aaron Lyons & Sneha Munshi & Sandaru M. Ileperuma & Dustin B. Ritchie & Noel Q. Hoffer & Abhishek Narayan & Michael T. Woodside, 2021. "Structural dynamics of single SARS-CoV-2 pseudoknot molecules reveal topologically distinct conformers," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Brian Houck-Loomis & Michael A. Durney & Carolina Salguero & Neelaabh Shankar & Julia M. Nagle & Stephen P. Goff & Victoria M. D’Souza, 2011. "An equilibrium-dependent retroviral mRNA switch regulates translational recoding," Nature, Nature, vol. 480(7378), pages 561-564, December.
    3. 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.
    4. 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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