RT Journal Article
SR Electronic
T1 Engineering a model cell for rational tuning of GPCR signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 390559
DO 10.1101/390559
A1 William M. Shaw
A1 Hitoshi Yamauchi
A1 Jack Mead
A1 Glen-Oliver F. Gowers
A1 David Öling
A1 Niklas Larsson
A1 Mark Wigglesworth
A1 Graham Ladds
A1 Tom Ellis
YR 2018
UL http://biorxiv.org/content/early/2018/08/13/390559.abstract
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.