ArticleMolecular biology and evolution2021
Were Ancestral Proteins Less Specific?
Article in Molecular biology and evolution, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Studying the evolutionary potential of ancestral aryl sulfatases in the alkaline phosphatase family with droplet microfluidics.The Analyst · 2026Article
- Evolutionary remodeling of the FXR binding pocket drove functional divergence and ligand discrimination.Molecular biology and evolution · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.Nature ecology & evolution · 2025Article
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.bioRxiv : the preprint server for biology · 2025Article
- Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters.Molecular biology and evolution · 2024Article
- Specialization restricts the evolutionary paths available to yeast sugar transporters.bioRxiv : the preprint server for biology · 2024Article
- Ancient nitrogenases are ATP dependent.mBio · 2024Article
- Calcium mediated static and dynamic allostery in S100A12: Implications for target recognition by S100 proteins.Protein science : a publication of the Protein Society · 2024Article
- Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022Review
- The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer.Molecular biology and evolution · 2022Article
- Ancestral reconstruction of duplicated signaling proteins reveals the evolution of signaling specificity.eLife · 2022Article
- Learning peptide recognition rules for a low-specificity protein.Protein science : a publication of the Protein Society · 2020Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Some have hypothesized that ancestral proteins were, on average, less specific than their descendants. If true, this would provide a universal axis along which to organize protein evolution and suggests that reconstructed ancestral proteins may be uniquely powerful tools for protein engineering. Ancestral sequence reconstruction studies are one line of evidence used to support this hypothesis. Previously, we performed such a study, investigating the evolution of peptide-binding specificity for the paralogs S100A5 and S100A6. The modern proteins appeared more specific than their last common ancestor (ancA5/A6), as each paralog bound a subset of the peptides bound by ancA5/A6. In this study, we revisit this transition, using quantitative phage display to measure the interactions of 30,533 random peptides with human S100A5, S100A6, and ancA5/A6. This unbiased screen reveals a different picture. While S100A5 and S100A6 do indeed bind to a subset of the peptides recognized by ancA5/A6, they also acquired new peptide partners outside of the set recognized by ancA5/A6. Our previous work showed that ancA5/A6 had lower specificity than its descendants when measured against biological targets; our new work shows that ancA5/A6 has similar specificity to the modern proteins when measured against a random set of peptide targets. This demonstrates that altered biological specificity does not necessarily indicate altered intrinsic specificity, and sounds a cautionary note for using ancestral reconstruction studies with biological targets as a means to infer global evolutionary trends in specificity.
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