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Epistasis shapes the fitness landscape of an allosteric specificity switch

View ORCID ProfileKyle K. Nishikawa, View ORCID ProfileNicholas Hoppe, View ORCID ProfileRobert Smith, View ORCID ProfileCraig Bingman, View ORCID ProfileSrivatsan Raman
doi: https://doi.org/10.1101/2020.10.21.348920
Kyle K. Nishikawa
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
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Nicholas Hoppe
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
3Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA
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Robert Smith
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
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Craig Bingman
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
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Srivatsan Raman
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
2Department of Bacteriology, University of Wisconsin-Madison, Madison, WI
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  • For correspondence: sraman4@wisc.edu
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Abstract

Epistasis is a major determinant in the emergence of novel protein function. In allosteric proteins, direct interactions between inducer-binding mutations propagate through the allosteric network, manifesting as epistasis at the level of biological function. Elucidating this relationship between local interactions and their global effects is essential to understanding evolution of allosteric proteins. We integrate computational design, structural and biophysical analysis to characterize the emergence of novel inducer specificity in an allosteric transcription factor. Adaptive landscapes of different inducers of the engineered mutant show that a few strong epistatic interactions constrain the number of viable sequence pathways, revealing ridges in the fitness landscape leading to new specificity. Crystallographic evidence shows a single mutation drives specificity by reshaping the binding pocket. Comparison of biophysical and functional landscapes emphasizes the nonlinear relationship between local inducer affinity and global function (allostery). Our results highlight the functional and evolutionary complexity of allosteric proteins.

Competing Interest Statement

The authors have declared no competing interest.

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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 October 21, 2020.
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Epistasis shapes the fitness landscape of an allosteric specificity switch
Kyle K. Nishikawa, Nicholas Hoppe, Robert Smith, Craig Bingman, Srivatsan Raman
bioRxiv 2020.10.21.348920; doi: https://doi.org/10.1101/2020.10.21.348920
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Epistasis shapes the fitness landscape of an allosteric specificity switch
Kyle K. Nishikawa, Nicholas Hoppe, Robert Smith, Craig Bingman, Srivatsan Raman
bioRxiv 2020.10.21.348920; doi: https://doi.org/10.1101/2020.10.21.348920

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