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Influenza A M2 Channel Oligomerization is Sensitive to its Chemical Environment

Julia A. Townsend, Henry M. Sanders, Amber D. Rolland, James S. Prell, Jun Wang, View ORCID ProfileMichael T. Marty
doi: https://doi.org/10.1101/2021.05.07.443160
Julia A. Townsend
1Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
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Henry M. Sanders
1Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
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Amber D. Rolland
2Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403, United States
3Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, United States
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James S. Prell
2Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403, United States
4Materials Science Institute, University of Oregon, Eugene, Oregon 97403, United States
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Jun Wang
5Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85721, United States
6Bio5 Institute, The University of Arizona, Tucson, Arizona 85721, United States
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Michael T. Marty
1Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
6Bio5 Institute, The University of Arizona, Tucson, Arizona 85721, United States
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  • ORCID record for Michael T. Marty
  • For correspondence: mtmarty@arizona.edu
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Abstract

Viroporins are small viral ion channels that play important roles in the viral infection cycle and are proven antiviral drug targets. Matrix protein 2 from influenza A (AM2) is the best characterized viroporin, and the current paradigm is that AM2 forms monodisperse tetramers. Here, we used native mass spectrometry, ion mobility spectrometry, and size-exclusion chromatography to characterize the oligomeric state of full-length AM2 in a variety of different pH and detergent conditions. Unexpectedly, we discovered that AM2 formed a range of different oligomeric complexes that were strongly influenced by its local chemical environment. The monodisperse tetramer was only observed in select conditions when the antiviral drug, amantadine, was added. Native mass spectrometry of AM2 in lipid nanodiscs with different lipids showed that lipids also affected the oligomeric states of AM2. Finally, nanodiscs uniquely enabled measurement of amantadine binding stoichiometries to AM2 in the intact lipid bilayer. These unexpected results reveal that AM2 forms a wider range of oligomeric states than previously thought possible, which provides new potential mechanisms of influenza pathology and pharmacology.

Significance Statement Many viruses contain small ion channels called viroporins that play diverse roles in viral infections. Influenza A M2 (AM2) is the best characterized viroporin and the target of the antivirals amantadine and rimantadine. Although past structural studies showed AM2 was a monodisperse tetramer, we discovered that AM2 forms polydisperse and dynamic oligomers that are highly sensitive to their local chemical environment. Our findings provide a new perspective on the structure and mechanisms of AM2 that may extend to other viroporins.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Classification: Biological Sciences: Biophysics and Computational Biology and Physical Sciences: Chemistry

  • https://figshare.com/articles/dataset/AM2_data_Figshare_zip/14558079

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 07, 2021.
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Influenza A M2 Channel Oligomerization is Sensitive to its Chemical Environment
Julia A. Townsend, Henry M. Sanders, Amber D. Rolland, James S. Prell, Jun Wang, Michael T. Marty
bioRxiv 2021.05.07.443160; doi: https://doi.org/10.1101/2021.05.07.443160
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Influenza A M2 Channel Oligomerization is Sensitive to its Chemical Environment
Julia A. Townsend, Henry M. Sanders, Amber D. Rolland, James S. Prell, Jun Wang, Michael T. Marty
bioRxiv 2021.05.07.443160; doi: https://doi.org/10.1101/2021.05.07.443160

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