Evolution-guided engineering of small-molecule biosensors

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.

doi:10.1093/nar/gkz954

Title: Evolution-guided engineering of small-molecule biosensors

Journal Article · Thu Nov 28 00:00:00 UTC 2019 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkz954 · OSTI ID:1605268

Snoek, Tim ^[1]; Chaberski, Evan K. ^[1]; Ambri, Francesca ^[1]; Kol, Stefan ^[1]; Bjørn, Sara P. ^[1]; Pang, Bo ^[2]; Barajas, Jesus F. ^[2];

^[1];

^[1]; Keasling, Jay D. ^[3]

Technical Univ. of Denmark, Lyngby (Denmark). Novo Nordisk Foundation Center for Biosustainability
Joint BioEnergy Institute, Emeryville, CA, USA
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

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1605268

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 1 Vol. 48; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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A general strategy to construct small molecule biosensors in eukaryotes Feng, Justin; Jester, Benjamin W.; Tinberg, Christine E. eLife, Vol. 4 https://doi.org/10.7554/eLife.10606	journal	December 2015

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