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Impact of initial protein stability on local fitness landscapes

Matthew S. Faber, Emily E. Wrenbeck, Laura R. Azouz, Paul J. Steiner, Timothy A. Whitehead
doi: https://doi.org/10.1101/590398
Matthew S. Faber
1Dept. Biochemistry and Molecular Biology
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Emily E. Wrenbeck
2Dept. of Chemical Engineering & Materials Science Michigan State University
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Laura R. Azouz
2Dept. of Chemical Engineering & Materials Science Michigan State University
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Paul J. Steiner
3Dept. of Chemical and Biological Engineering, University of Colorado, Boulder, CO
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Timothy A. Whitehead
2Dept. of Chemical Engineering & Materials Science Michigan State University
3Dept. of Chemical and Biological Engineering, University of Colorado, Boulder, CO
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  • For correspondence: timothy.whitehead@colorado.edu
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Abstract

It is incompletely understood how biophysical properties like protein stability impact molecular evolution and epistasis. Epistasis is defined as specific when a mutation exclusively influences the phenotypic effect of another mutation, often at physically interacting residues. By contrast, nonspecific epistasis results when a mutation is influenced by a large number of non-local mutations. As most mutations are pleiotropic, basal protein stability is thought to determine activity-enhancing mutational tolerance, which implies that nonspecific epistasis is dominant. However, evidence exists for both specific and nonspecific epistasis as the prevalent factor, with limited comprehensive datasets to validate either claim. Here we use deep mutational scanning to probe how initial enzyme stability impacts local fitness landscapes. We computationally designed two different variants of the amidase AmiE in which catalytic efficiencies are statistically indistinguishable but the enzyme variants have lower probabilities of folding in vivo. Local fitness landscapes show only slight alterations among variants, with essentially the same global distribution of fitness effects. However, specific epistasis was predominant for the subset of mutations exhibiting positive sign epistasis. These mutations mapped to spatially distinct locations on AmiE near the initial mutation or proximal to the active site. Most intriguingly, the majority of specific epistatic mutations were codon-dependent, with different synonymous codons resulting in fitness sign reversals. Together, these results offer a nuanced view of how protein stability impacts local fitness landscapes, and suggest that transcriptional-translational effects are an equally important determinant as thermodynamic stability in determining evolutionary outcomes.

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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-NC-ND 4.0 International license.
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Posted March 26, 2019.
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Impact of initial protein stability on local fitness landscapes
Matthew S. Faber, Emily E. Wrenbeck, Laura R. Azouz, Paul J. Steiner, Timothy A. Whitehead
bioRxiv 590398; doi: https://doi.org/10.1101/590398
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Impact of initial protein stability on local fitness landscapes
Matthew S. Faber, Emily E. Wrenbeck, Laura R. Azouz, Paul J. Steiner, Timothy A. Whitehead
bioRxiv 590398; doi: https://doi.org/10.1101/590398

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