Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9
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 func...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/54100 |
| _version_ | 1811236192585252864 |
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| author | Joseph L Harman Andrea N Loes Gus D Warren Maureen C Heaphy Kirsten J Lampi Michael J Harms |
| author_facet | Joseph L Harman Andrea N Loes Gus D Warren Maureen C Heaphy Kirsten J Lampi Michael J Harms |
| author_sort | Joseph L Harman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:04:42Z |
| format | Article |
| id | doaj.art-88609f02bbf54d8881dce90510c75b32 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:04:42Z |
| publishDate | 2020-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-88609f02bbf54d8881dce90510c75b322022-12-22T03:33:45ZengeLife Sciences Publications LtdeLife2050-084X2020-04-01910.7554/eLife.54100Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9Joseph L Harman0https://orcid.org/0000-0002-8283-0301Andrea N Loes1Gus D Warren2Maureen C Heaphy3Kirsten J Lampi4Michael J Harms5https://orcid.org/0000-0002-0241-4122Department of Chemistry and Biochemistry, University of Oregon, Eugene, United States; Institute of Molecular Biology, University of Oregon, Eugene, United StatesDepartment of Chemistry and Biochemistry, University of Oregon, Eugene, United States; Institute of Molecular Biology, University of Oregon, Eugene, United StatesDepartment of Chemistry and Biochemistry, University of Oregon, Eugene, United States; Institute of Molecular Biology, University of Oregon, Eugene, United StatesDepartment of Chemistry and Biochemistry, University of Oregon, Eugene, United States; Institute of Molecular Biology, University of Oregon, Eugene, United StatesOregon Health & Science University, Portland, United StatesDepartment of Chemistry and Biochemistry, University of Oregon, Eugene, United States; Institute of Molecular Biology, University of Oregon, Eugene, United StatesMultifunctional 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.https://elifesciences.org/articles/54100protein evolutionpleiotropyancestral sequence reconstructioninflammationantimicrobial activitymammals |
| spellingShingle | Joseph L Harman Andrea N Loes Gus D Warren Maureen C Heaphy Kirsten J Lampi Michael J Harms Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 eLife protein evolution pleiotropy ancestral sequence reconstruction inflammation antimicrobial activity mammals |
| title | Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 |
| title_full | Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 |
| title_fullStr | Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 |
| title_full_unstemmed | Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 |
| title_short | Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9 |
| title_sort | evolution of multifunctionality through a pleiotropic substitution in the innate immune protein s100a9 |
| topic | protein evolution pleiotropy ancestral sequence reconstruction inflammation antimicrobial activity mammals |
| url | https://elifesciences.org/articles/54100 |
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