ArticleeLife2020
Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- Formation of the intradimer disulfide bond in human calprotectin maintains metal-withholding function and tunes proteolytic susceptibility.Chemical science · 2026Article
- Exploration of genes and identification of evolutionary evidence in adeno-associated viruses.Journal of microbiology (Seoul, Korea) · 2026Article
- Zebrafish do not have a calprotectin ortholog.PloS one · 2025Article
- Survival prediction in patients with head and neck squamous cell carcinoma and novel mechanistic insights of S100A8/A9.Discover oncology · 2024Article
- Changing expression system alters oligomerization and proinflammatory activity of recombinant human S100A9.bioRxiv : the preprint server for biology · 2024Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- In Silico Intensive Analysis for the E4 Gene Evolution of Human Adenovirus Species D.Journal of microbiology (Seoul, Korea) · 2024Article
- Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution.PLoS computational biology · 2023Article
- Topiary: Pruning the manual labor from ancestral sequence reconstruction.Protein science : a publication of the Protein Society · 2023Article
- DecreasedPeerJ · 2023Article
- Current progress on innate immune evasion mediated by NFrontiers in immunology · 2023Review
- Evolutionary entrenchment in immune proteins selects against stabilizing mutations.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Evolution avoids a pathological stabilizing interaction in the immune protein S100A9.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Fabrication and Characterization of pcDNA3.1(+) Location within Chitosan/Nanoparticles Complexes for Enhanced Gene Delivery.Iranian journal of biotechnology · 2022Article
- Review
- Antimicrobial peptides: Defending the mucosal epithelial barrier.Frontiers in oral health · 2022Review
- Molecular Evolution of Transition Metal Bioavailability at the Host-Pathogen Interface.Trends in microbiology · 2021Review
- S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation.Science advances · 2021Article
- Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins.The Journal of biological chemistry · 2020Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.