Engineering a Model Cell for Rational Tuning of GPCR Signaling.

Autor:	Shaw WM; Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK., Yamauchi H; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK., Mead J; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK., Gowers GF; Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK., Bell DJ; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK; SynbiCITE Innovation and Knowledge Centre, Imperial College London, London SW7 2AZ, UK., Öling D; Discovery Biology, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D, 431 50 Mölndal, Sweden., Larsson N; Discovery Biology, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D, 431 50 Mölndal, Sweden., Wigglesworth M; Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, UK. Electronic address: mark.wigglesworth@astrazeneca.com., Ladds G; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK. Electronic address: grl30@cam.ac.uk., Ellis T; Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK. Electronic address: t.ellis@imperial.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2019 Apr 18; Vol. 177 (3), pp. 782-796.e27. Date of Electronic Publication: 2019 Apr 04.
DOI:	10.1016/j.cell.2019.02.023
Abstrakt:	G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond to specific cues in their environment. However, the relationship between stimulus and response for each GPCR is difficult to predict due to diversity in natural signal transduction architecture and expression. Using genome engineering in yeast, we constructed an insulated, modular GPCR signal transduction system to study how the response to stimuli can be predictably tuned using synthetic tools. We delineated the contributions of a minimal set of key components via computational and experimental refactoring, identifying simple design principles for rationally tuning the dose response. Using five different GPCRs, we demonstrate how this enables cells and consortia to be engineered to respond to desired concentrations of peptides, metabolites, and hormones relevant to human health. This work enables rational tuning of cell sensing while providing a framework to guide reprogramming of GPCR-based signaling in other systems. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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