Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9
- University of Oregon, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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.
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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Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9
eLife 9:e54100.
https://doi.org/10.7554/eLife.54100
