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Were ancestral proteins less specific?

View ORCID ProfileLucas C. Wheeler, View ORCID ProfileMichael J. Harms
doi: https://doi.org/10.1101/2020.05.27.120261
Lucas C. Wheeler
1Institute of Molecular Biology, University of Oregon, Eugene OR 97403
2Department of Chemistry and Biochemistry, University of Oregon, Eugene OR 97403
3Department of Ecology and Evolutionary Biology, University of Colorado, Boulder CO 80309
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Michael J. Harms
1Institute of Molecular Biology, University of Oregon, Eugene OR 97403
2Department of Chemistry and Biochemistry, University of Oregon, Eugene OR 97403
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  • For correspondence: harms@uoregon.edu
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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 the current study, we revisit this transition, using quantitative phage display to measure the interactions of 19,194 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 30, 2020.
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Were ancestral proteins less specific?
Lucas C. Wheeler, Michael J. Harms
bioRxiv 2020.05.27.120261; doi: https://doi.org/10.1101/2020.05.27.120261
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Were ancestral proteins less specific?
Lucas C. Wheeler, Michael J. Harms
bioRxiv 2020.05.27.120261; doi: https://doi.org/10.1101/2020.05.27.120261

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