Structure-based design of stabilized recombinant influenza neuraminidase tetramers

Daniel Ellis, Julia Lederhofer, Oliver J. Acton, Yaroslav Tsybovsky, Sally Kephart, Christina Yap, Rebecca A. Gillespie, Adrian Creanga, Audrey Olshefsky, Tyler Stephens, Deleah Pettie, Michael Murphy, Claire Sydeman, Maggie Ahlrichs, Sidney Chan, Andrew J. Borst, Young-Jun Park, Kelly K. Lee, Barney S. Graham, David Veesler, Neil P. King () and Masaru Kanekiyo ()
Additional contact information
Daniel Ellis: University of Washington
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
Tyler Stephens: Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute
Deleah Pettie: University of Washington
Michael Murphy: University of Washington
Claire Sydeman: University of Washington
Maggie Ahlrichs: University of Washington
Sidney Chan: University of Washington
Andrew J. Borst: University of Washington
Young-Jun Park: University of Washington
Kelly K. Lee: University of Washington
Barney S. Graham: National Institutes of Health
David Veesler: University of Washington
Neil P. King: University of Washington
Masaru Kanekiyo: National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29416-z

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