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Structure-based design of stabilized recombinant influenza neuraminidase tetramers

Author

Listed:
  • Daniel Ellis

    (University of Washington
    University of Washington
    University of Washington
    Icosavax Inc.)

  • Julia Lederhofer

    (National Institutes of Health)

  • Oliver J. Acton

    (University of Washington)

  • Yaroslav Tsybovsky

    (Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute)

  • Sally Kephart

    (University of Washington)

  • Christina Yap

    (National Institutes of Health)

  • Rebecca A. Gillespie

    (National Institutes of Health)

  • Adrian Creanga

    (National Institutes of Health)

  • Audrey Olshefsky

    (University of Washington
    University of Washington)

  • Tyler Stephens

    (Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute)

  • Deleah Pettie

    (University of Washington
    University of Washington)

  • Michael Murphy

    (University of Washington
    University of Washington)

  • Claire Sydeman

    (University of Washington
    University of Washington)

  • Maggie Ahlrichs

    (University of Washington
    University of Washington)

  • Sidney Chan

    (University of Washington
    University of Washington)

  • Andrew J. Borst

    (University of Washington
    University of Washington)

  • Young-Jun Park

    (University of Washington
    University of Washington)

  • Kelly K. Lee

    (University of Washington)

  • Barney S. Graham

    (National Institutes of Health)

  • David Veesler

    (University of Washington
    University of Washington)

  • Neil P. King

    (University of Washington
    University of Washington)

  • Masaru Kanekiyo

    (National Institutes of Health)

Abstract

Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an “open” state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the “closed” state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.

Suggested Citation

  • Daniel Ellis & Julia Lederhofer & Oliver J. Acton & Yaroslav Tsybovsky & Sally Kephart & Christina Yap & Rebecca A. Gillespie & Adrian Creanga & Audrey Olshefsky & Tyler Stephens & Deleah Pettie & Mic, 2022. "Structure-based design of stabilized recombinant influenza neuraminidase tetramers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29416-z
    DOI: 10.1038/s41467-022-29416-z
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    References listed on IDEAS

    as
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