PT  - JOURNAL ARTICLE
AU  - William M. Shaw
AU  - Hitoshi Yamauchi
AU  - Jack Mead
AU  - Glen-Oliver F. Gowers
AU  - David Öling
AU  - Niklas Larsson
AU  - Mark Wigglesworth
AU  - Graham Ladds
AU  - Tom Ellis
TI  - Engineering a model cell for rational tuning of GPCR signaling
AID  - 10.1101/390559
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 390559
4099  - http://biorxiv.org/content/early/2018/08/13/390559.short
4100  - http://biorxiv.org/content/early/2018/08/13/390559.full
AB  - 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 here 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 four different receptors, 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 more complex systems.