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Title: Evolution-guided engineering of small-molecule biosensors

Abstract

Allosteric transcription factors (aTFs) have proven widely applicable for biotechnology and synthetic biology as ligand-specific biosensors enabling real-time monitoring, selection and regulation of cellular metabolism. However, both the biosensor specificity and the correlation between ligand concentration and biosensor output signal, also known as the transfer function, often needs to be optimized before meeting application needs. Here, we present a versatile and high-throughput method to evolve prokaryotic aTF specificity and transfer functions in a eukaryote chassis, namely baker's yeast Saccharomyces cerevisiae. From a single round of mutagenesis of the effector-binding domain (EBD) coupled with various toggled selection regimes, we robustly select aTF variants of the cis,cis-muconic acid-inducible transcription factor BenM evolved for change in ligand specificity, increased dynamic output range, shifts in operational range, and a complete inversion-of-function from activation to repression. Importantly, by targeting only the EBD, the evolved biosensors display DNA-binding affinities similar to BenM, and are functional when ported back into a prokaryotic chassis. The developed platform technology thus leverages aTF evolvability for the development of new host-agnostic biosensors with user-defined small-molecule specificities and transfer functions.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [2]; ORCiD logo [1]; ORCiD logo [1];  [3]
+ Show Author Affiliations
  1. Technical Univ. of Denmark, Lyngby (Denmark). Novo Nordisk Foundation Center for Biosustainability
  2. Joint BioEnergy Institute, Emeryville, CA, USA
  3. Technical Univ. of Denmark, Lyngby (Denmark). Novo Nordisk Foundation Center for Biosustainability; Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States); Shenzhen Inst. of Advanced Technologies, Shenzhen (China). Inst. for Synthetic Biology
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1605268
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 48; Journal Issue: 1; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Synthetic Biology and Assembly Cloning

Citation Formats

Snoek, Tim, Chaberski, Evan K., Ambri, Francesca, Kol, Stefan, Bjørn, Sara P., Pang, Bo, Barajas, Jesus F., Welner, Ditte H., Jensen, Michael K., and Keasling, Jay D. Evolution-guided engineering of small-molecule biosensors. United States: N. p., 2019. Web. doi:10.1093/nar/gkz954.
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Snoek, Tim, Chaberski, Evan K., Ambri, Francesca, Kol, Stefan, Bjørn, Sara P., Pang, Bo, Barajas, Jesus F., Welner, Ditte H., Jensen, Michael K., & Keasling, Jay D. Evolution-guided engineering of small-molecule biosensors. United States. https://doi.org/10.1093/nar/gkz954
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Snoek, Tim, Chaberski, Evan K., Ambri, Francesca, Kol, Stefan, Bjørn, Sara P., Pang, Bo, Barajas, Jesus F., Welner, Ditte H., Jensen, Michael K., and Keasling, Jay D. Thu . "Evolution-guided engineering of small-molecule biosensors". United States. https://doi.org/10.1093/nar/gkz954. https://www.osti.gov/servlets/purl/1605268.
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@article{osti_1605268,
title = {Evolution-guided engineering of small-molecule biosensors},
author = {Snoek, Tim and Chaberski, Evan K. and Ambri, Francesca and Kol, Stefan and Bjørn, Sara P. and Pang, Bo and Barajas, Jesus F. and Welner, Ditte H. and Jensen, Michael K. and Keasling, Jay D.},
abstractNote = {Allosteric transcription factors (aTFs) have proven widely applicable for biotechnology and synthetic biology as ligand-specific biosensors enabling real-time monitoring, selection and regulation of cellular metabolism. However, both the biosensor specificity and the correlation between ligand concentration and biosensor output signal, also known as the transfer function, often needs to be optimized before meeting application needs. Here, we present a versatile and high-throughput method to evolve prokaryotic aTF specificity and transfer functions in a eukaryote chassis, namely baker's yeast Saccharomyces cerevisiae. From a single round of mutagenesis of the effector-binding domain (EBD) coupled with various toggled selection regimes, we robustly select aTF variants of the cis,cis-muconic acid-inducible transcription factor BenM evolved for change in ligand specificity, increased dynamic output range, shifts in operational range, and a complete inversion-of-function from activation to repression. Importantly, by targeting only the EBD, the evolved biosensors display DNA-binding affinities similar to BenM, and are functional when ported back into a prokaryotic chassis. The developed platform technology thus leverages aTF evolvability for the development of new host-agnostic biosensors with user-defined small-molecule specificities and transfer functions.},
doi = {10.1093/nar/gkz954},
journal = {Nucleic Acids Research},
number = 1,
volume = 48,
place = {United States},
year = {Thu Nov 28 00:00:00 EST 2019},
month = {Thu Nov 28 00:00:00 EST 2019}
}
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https://doi.org/10.1093/nar/gkz954
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Fourteen Ways to Reroute Cooperative Communication in the Lactose Repressor: Engineering Regulatory Proteins with Alternate Repressive Functions
journal, September 2016

Perturbation from a Distance:  Mutations that Alter LacI Function through Long-Range Effects †
journal, December 2003

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journal, July 2014

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Dual selection enhances the signaling specificity of a variant of the quorum-sensing transcriptional activator LuxR
journal, May 2006

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journal, December 2002

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Biosensor libraries harness large classes of binding domains for construction of allosteric transcriptional regulators
journal, August 2018

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Trp-ing upon new repressors
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Improvement of the reverse tetracycline transactivator by single amino acid substitutions that reduce leaky target gene expression to undetectable levels
journal, June 2016

  • Roney, Ian J.; Rudner, Adam D.; Couture, Jean-François
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journal, May 2002

  • Bundy, B. M.; Collier, L. S.; Hoover, T. R.
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  • DOI: 10.1073/pnas.102605799

Isolation of the lac Repressor
journal, December 1966

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  • DOI: 10.1073/pnas.56.6.1891

Gel retardation at low pH resolves trp repressor-DNA complexes for quantitative study.
journal, February 1988

Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
journal, June 1992

  • Gossen, M.; Bujard, H.
  • Proceedings of the National Academy of Sciences, Vol. 89, Issue 12
  • DOI: 10.1073/pnas.89.12.5547

The rational design of allosteric interactions in a monomeric protein and its applications to the construction of biosensors
journal, April 1997

  • Marvin, J. S.; Corcoran, E. E.; Hattangadi, N. A.
  • Proceedings of the National Academy of Sciences, Vol. 94, Issue 9
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InterPro in 2017—beyond protein family and domain annotations
journal, November 2016

  • Finn, Robert D.; Attwood, Teresa K.; Babbitt, Patricia C.
  • Nucleic Acids Research, Vol. 45, Issue D1
  • DOI: 10.1093/nar/gkw1107

Structure and function of the LysR-type transcriptional regulator (LTTR) family proteins
journal, December 2008

Modular organisation of inducer recognition and allostery in the tetracycline repressor
journal, April 2016

  • Werten, Sebastiaan; Schneider, Julia; Palm, Gottfried Julius
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  • DOI: 10.1111/febs.13723

Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes
journal, April 1996

Combinatorial Synthesis of Genetic Networks
journal, May 2002

Structural characterization and corepressor binding of the Escherichia coli purine repressor.
journal, January 1992

Promoter Nucleosome Organization Shapes the Evolution of Gene Expression
journal, March 2012

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