Engineering an allosteric transcription factor to respond to new ligands

Taylor, Noah D.; Garruss, Alexander S.; Moretti, Rocco; Chan, Sum; Arbing, Mark A.; Cascio, Duilio; Rogers, Jameson K.; Isaacs, Farren J.; Kosuri, Sriram; Baker, David; Fields, Stanley; Church, George M.; Raman, Srivatsan

doi:10.1038/nmeth.3696

Title: Engineering an allosteric transcription factor to respond to new ligands

Journal Article · 20 December 2015 · Nature Methods

DOI: https://doi.org/10.1038/nmeth.3696 · OSTI ID:1239401

Taylor, Noah D. ^[1]; Garruss, Alexander S. ^[1]; Moretti, Rocco ^[2]; Chan, Sum ^[3]; Arbing, Mark A. ^[3]; Cascio, Duilio ^[3]; Rogers, Jameson K. ^[1]; Isaacs, Farren J. ^[4];

^[5]; Baker, David ^[2]; Fields, Stanley ^[6]; Church, George M. ^[1]; Raman, Srivatsan ^[1]

Harvard Univ., Boston, MA (United States). Wyss Inst. for Biologically-Inspired Engineering; Harvard Medical School, Boston, MA (United States). Dept. of Genetics
Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry. Howard Hughes Medical Inst.
Univ. of California, Los Angeles, CA (United States). UCLA-USDOE Inst. for Genomics and Proteomics
Yale Univ., New Haven, CT (United States). Dept. of Molecular, Cellular and Developmental Biology; Yale Univ., West Haven, CT (United States). Systems Biology Inst.
Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry
Univ. of Washington, Seattle, WA (United States). Dept. of Genome Sciences. Dept. of Medicine. Howard Hughes Medical Inst.

Genetic regulatory proteins inducible by small molecules are useful synthetic biology tools as sensors and switches. Bacterial allosteric transcription factors (aTFs) are a major class of regulatory proteins, but few aTFs have been redesigned to respond to new effectors beyond natural aTF-inducer pairs. Altering inducer specificity in these proteins is difficult because substitutions that affect inducer binding may also disrupt allostery. In this paper, we engineered an aTF, the Escherichia coli lac repressor, LacI, to respond to one of four new inducer molecules: fucose, gentiobiose, lactitol and sucralose. Using computational protein design, single-residue saturation mutagenesis or random mutagenesis, along with multiplex assembly, we identified new variants comparable in specificity and induction to wild-type LacI with its inducer, isopropyl β-D-1-thiogalactopyranoside (IPTG). Finally, the ability to create designer aTFs will enable applications including dynamic control of cell metabolism, cell biology and synthetic gene circuits.

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Research Organization:: Harvard Univ., Boston, MA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States)

Contributing Organization:: Yale Univ., New Haven, CT (United States); Univ. of California, Los Angeles, CA (United States); Univ. of Washington, Seattle, WA (United States)

Grant/Contract Number:: FG02-02ER63445; FC02-02ER63421; AC02-06CH11357

OSTI ID:: 1239401

Journal Information:: Nature Methods, Journal Name: Nature Methods Journal Issue: 2 Vol. 13; ISSN 1548-7091

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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A microbial sensor for organophosphate hydrolysis exploiting an engineered specificity switch in a transcription factor Jha, Ramesh K.; Kern, Theresa L.; Kim, Youngchang Nucleic Acids Research, Vol. 44, Issue 17 https://doi.org/10.1093/nar/gkw687	journal	August 2016
Tools and systems for evolutionary engineering of biomolecules and microorganisms Jang, Sungho; Kim, Minsun; Hwang, Jaeseong Journal of Industrial Microbiology & Biotechnology, Vol. 46, Issue 9-10 https://doi.org/10.1007/s10295-019-02191-5	journal	May 2019
Phosphatase activity tunes two-component system sensor detection threshold Landry, Brian P.; Palanki, Rohan; Dyulgyarov, Nikola Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03929-y	journal	April 2018
Sort-Seq Approach to Engineering a Formaldehyde-Inducible Promoter for Dynamically Regulated Escherichia coli Growth on Methanol Rohlhill, Julia; Sandoval, Nicholas R.; Papoutsakis, Eleftherios T. ACS Synthetic Biology, Vol. 6, Issue 8, p. 1584-1595 https://doi.org/10.1021/acssynbio.7b00114	journal	May 2017
A self-inducible heterologous protein expression system in Escherichia coli Briand, L.; Marcion, G.; Kriznik, A. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep33037	journal	September 2016
Genetically encoded biosensors for lignocellulose valorization Alvarez-Gonzalez, Guadalupe; Dixon, Neil Biotechnology for Biofuels, Vol. 12, Issue 1 https://doi.org/10.1186/s13068-019-1585-6	journal	October 2019
Archimedes’ principle for characterisation of recombinant whole cell biocatalysts Schmitt, Steven; Walser, Marcel; Rehmann, Michael Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-20877-1	journal	February 2018
Archimedes’ principle for characterisation of recombinant whole cell biocatalysts Schmitt, Steven; Walser, Marcel; Rehmann, Michael ETH Zurich https://doi.org/10.3929/ethz-b-000242671	text	January 2018
A paper-based, cell-free biosensor system for the detection of heavy metals and date rape drugs Gräwe, Alexander; Dreyer, Anna; Vornholt, Tobias PLOS ONE, Vol. 14, Issue 3 https://doi.org/10.1371/journal.pone.0210940	journal	March 2019
Parallel Screening for Rapid Identification of Orthogonal Bioluminescent Tools Rathbun, Colin M.; Porterfield, William B.; Jones, Krysten A. ACS Central Science, Vol. 3, Issue 12 https://doi.org/10.1021/acscentsci.7b00394	journal	November 2017
Positive-feedback, ratiometric biosensor expression improves high-throughput metabolite-producer screening efficiency in yeast Williams, Thomas C.; Xu, Xin; Ostrowski, Martin Synthetic Biology, Vol. 2, Issue 1 https://doi.org/10.1093/synbio/ysw002	journal	January 2017
Archimedes’ principle for characterisation of recombinant whole cell biocatalysts Schmitt, Steven; Walser, Marcel; Rehmann, Michael ETH Zurich https://doi.org/10.3929/ethz-b-000242671	text	January 2018
The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology Bojar, Daniel; Fussenegger, Martin ETH Zurich https://doi.org/10.3929/ethz-b-000426938	text	January 2020
Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein Schmidt, Karin; Gardill, Bernd R.; Kern, Alina Proceedings of the National Academy of Sciences, Vol. 115, Issue 22 https://doi.org/10.1073/pnas.1716666115	journal	May 2018
Unified rational protein engineering with sequence-based deep representation learning Alley, Ethan C.; Khimulya, Grigory; Biswas, Surojit Nature Methods, Vol. 16, Issue 12 https://doi.org/10.1038/s41592-019-0598-1	journal	October 2019
Riboregulated toehold-gated gRNA for programmable CRISPR–Cas9 function Siu, Ka-Hei; Chen, Wilfred Nature Chemical Biology, Vol. 15, Issue 3 https://doi.org/10.1038/s41589-018-0186-1	journal	December 2018
MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect Esposito, Daniel; Weile, Jochen; Shendure, Jay Genome Biology, Vol. 20, Issue 1 https://doi.org/10.1186/s13059-019-1845-6	journal	November 2019
Directed evolution of the PcaV allosteric transcription factor to generate a biosensor for aromatic aldehydes F. M. Machado, Leopoldo; Currin, Andrew; Dixon, Neil Journal of Biological Engineering, Vol. 13, Issue 1 https://doi.org/10.1186/s13036-019-0214-z	journal	November 2019
Programmable T7-based synthetic transcription factors Hussey, Brendan J.; McMillen, David R. Nucleic Acids Research, Vol. 46, Issue 18 https://doi.org/10.1093/nar/gky785	journal	August 2018
Synthetic addiction extends the productive life time of engineered Escherichia coli populations Rugbjerg, Peter; Sarup-Lytzen, Kira; Nagy, Mariann Proceedings of the National Academy of Sciences, Vol. 115, Issue 10 https://doi.org/10.1073/pnas.1718622115	journal	February 2018
Converting a Periplasmic Binding Protein into a Synthetic Biosensing Switch through Domain Insertion Ribeiro, Lucas F.; Amarelle, Vanesa; Ribeiro, Liliane F. C. BioMed Research International, Vol. 2019 https://doi.org/10.1155/2019/4798793	journal	January 2019
The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology Bojar, Daniel; Fussenegger, Martin Small, Vol. 16, Issue 27 https://doi.org/10.1002/smll.201903093	journal	October 2019
Synthetic Biology-The Synthesis of Biology Ausländer, Simon; Ausländer, David; Fussenegger, Martin Angewandte Chemie International Edition, Vol. 56, Issue 23 https://doi.org/10.1002/anie.201609229	journal	April 2017
Structural and functional analyses of the cellulase transcription regulator CelR Fu, Yaoyao; Yeom, Soo‐Jin; Kwon, Kil Koang FEBS Letters, Vol. 592, Issue 16 https://doi.org/10.1002/1873-3468.13206	journal	August 2018
Binary addition in a living cell based on riboregulation Rosado, Arantxa; Cordero, Teresa; Rodrigo, Guillermo PLOS Genetics, Vol. 14, Issue 7 https://doi.org/10.1371/journal.pgen.1007548	journal	July 2018

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Title: Engineering an allosteric transcription factor to respond to new ligands

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