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Cell

Title:		Engineering a Model Cell for Rational Tuning of GPCR Signaling
Author(s):		Shaw WM; Yamauchi H; Mead J; Gowers GF; Bell DJ; Oling D; Larsson N; Wigglesworth M; Ladds G; Ellis T;
Address:		"Department of Bioengineering, Imperial College London, London SW7 2AZ, UK; Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK. Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK; SynbiCITE Innovation and Knowledge Centre, Imperial College London, London SW7 2AZ, UK. Discovery Biology, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D, 431 50 Molndal, Sweden. Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, UK. Electronic address: mark.wigglesworth@astrazeneca.com. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK. Electronic address: grl30@cam.ac.uk. 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"
Journal Title:		Cell
Year:		2019
Volume:		20190404
Issue:		3
Page Number:		782 - 796
DOI:		10.1016/j.cell.2019.02.023
ISSN/ISBN:		1097-4172 (Electronic) 0092-8674 (Print) 0092-8674 (Linking)
Abstract:		"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"
Keywords:		"Gene Expression/drug effects Genetic Engineering Humans Pheromones/pharmacology Receptors, G-Protein-Coupled/*metabolism Saccharomyces cerevisiae/metabolism Saccharomyces cerevisiae Proteins/genetics/metabolism *Signal Transduction/drug effects Transcript;"
Notes:		"MedlineShaw, William M Yamauchi, Hitoshi Mead, Jack Gowers, Glen-Oliver F Bell, David J Oling, David Larsson, Niklas Wigglesworth, Mark Ladds, Graham Ellis, Tom eng BB/M503381/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom BB/M00015X/2/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom Research Support, Non-U.S. Gov't 2019/04/09 Cell. 2019 Apr 18; 177(3):782-796.e27. doi: 10.1016/j.cell.2019.02.023. Epub 2019 Apr 4"