| First Author | Harman JL | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32255429 | Mgi Jnum | J:290879 |
| Mgi Id | MGI:6443220 | Doi | 10.7554/eLife.54100 |
| Citation | Harman JL, et al. (2020) Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9. Elife 9:e54100 |
| abstractText | 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 four 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. |
