D614G mutation alters SARS-CoV-2 spike conformational dynamics and protease cleavage susceptibility at the S1/S2 junction

  1. Sophie M-C. Gobeil
  2. Katarzyna Janowska
  3. Shana McDowell
  4. Katayoun Mansouri
  5. Robert Parks
  6. Kartik Manne
  7. Victoria Stalls
  8. Megan Kopp
  9. Rory Henderson
  10. Robert J Edwards
  11. Barton F. Haynes
  12. Priyamvada Acharya

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

The SARS-CoV-2 spike (S) protein is the target of vaccine design efforts to end the COVID-19 pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic, and are now the dominant form worldwide. Here, we analyze the D614G mutation in the context of a soluble S ectodomain construct. Cryo-EM structures, antigenicity and proteolysis experiments suggest altered conformational dynamics resulting in enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage altered the conformational dynamics of the Receptor Binding Domains (RBD) in the G614 S ectodomain, demonstrating an allosteric effect on the RBD dynamics triggered by changes in the SD2 region, that harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 spike conformational dynamics and allostery, and have implications for vaccine design.

Highlights

  • SARS-CoV-2 S ectodomains with or without the K986P, V987P mutations have similar structures, antigenicity and stability.

  • The D614G mutation alters S protein conformational dynamics.

  • D614G enhances protease cleavage susceptibility at the S protein furin cleavage site.

  • Cryo-EM structures reveal allosteric effect of changes at the S1/S2 junction on RBD dynamics.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.10.11.335299: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations of this study: In this paper, we study the effect of the D614G mutation on RBD dynamics and susceptibility to furin cleavage. We find that the D614G mutation results in increased furin cleavage susceptibility, which could be responsible for the increased transmissibility of the SARS-CoV-2 with the D614G mutation. It is important to consider though that these results are obtained in the context of an engineered soluble construct and further studies are needed to understand if these effects translate to the native virion context.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.10.11.335299 on bioRxiv