Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

  1. Joseph L Harman
  2. Andrea N Loes
  3. Gus D Warren
  4. Maureen C Heaphy
  5. Kirsten J Lampi
  6. Michael J Harms  Is a corresponding author
  1. University of Oregon, United States
  2. Oregon Health and Sciences University, United States

Abstract

Multifunctional proteins are evolutionary puzzles: how do proteins evolve to satisfy multiple functional constraints? S100A9 is one such multifunctional protein. It potently amplifies inflammation via Toll-like receptor 4 and is antimicrobial as part of a heterocomplex with S100A8. These two functions are seemingly regulated by proteolysis: S100A9 is readily degraded, while S100A8/S100A9 is resistant. We take an evolutionary biochemical approach to show that S100A9 evolved both functions and lost proteolytic resistance from a weakly proinflammatory, proteolytically resistant amniote ancestor. We identify a historical substitution that has pleiotropic effects on S100A9 proinflammatory activity and proteolytic resistance but has little effect on S100A8/S100A9 antimicrobial activity. We thus propose that mammals evolved S100A8/S100A9 antimicrobial and S100A9 proinflammatory activities concomitantly with a proteolytic 'timer' to selectively regulate S100A9. This highlights how the same mutation can have pleiotropic effects on one functional state of a protein but not another, thus facilitating the evolution of multifunctionality.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Joseph L Harman

    Department of Chemistry and Biochemistry/Institute of Molecular Biology, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8283-0301
  2. Andrea N Loes

    Department of Chemistry and Biochemistry/Institute of Molecular Biology, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gus D Warren

    Department of Chemistry and Biochemistry/Institute of Molecular Biology, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Maureen C Heaphy

    Department of Chemistry and Biochemistry/Institute of Molecular Biology, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kirsten J Lampi

    School of Dentistry, Oregon Health and Sciences University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael J Harms

    Department of Chemistry and Biochemistry/Institute of Molecular Biology, University of Oregon, Eugene, United States
    For correspondence
    harms@uoregon.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0241-4122

Funding

American Heart Association (16 15BGIA22830013)

  • Michael J Harms

Pew Charitable Trusts

  • Michael J Harms

National Institutes of Health (3R01GM117140-03S1)

  • Michael J Harms

National Institutes of Health (T32GM007413)

  • Joseph L Harman

National Institutes of Health (T32GM007413)

  • Andrea N Loes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael T Laub, Massachusetts Institute of Technology, United States

Publication history

  1. Received: December 2, 2019
  2. Accepted: April 3, 2020
  3. Accepted Manuscript published: April 7, 2020 (version 1)
  4. Version of Record published: May 11, 2020 (version 2)

Copyright

© 2020, Harman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joseph L Harman
  2. Andrea N Loes
  3. Gus D Warren
  4. Maureen C Heaphy
  5. Kirsten J Lampi
  6. Michael J Harms
(2020)
Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9
eLife 9:e54100.
https://doi.org/10.7554/eLife.54100

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