title: Synthetic conversion of a graded receptor signal into a tunable, reversible switch.
abstract: The ability to engineer an all-or-none cellular response to a given signaling ligand is important in applications ranging from biosensing to tissue engineering. However, synthetic gene network 'switches' have been limited in their applicability and tunability due to their reliance on specific components to function. Here, we present a strategy for reversible switch design that instead relies only on a robust, easily constructed network topology with two positive feedback loops and we apply the method to create highly ultrasensitive (n(H)>20), bistable cellular responses to a synthetic ligand/receptor complex. Independent modulation of the two feedback strengths enables rational tuning and some decoupling of steady-state (ultrasensitivity, signal amplitude, switching threshold, and bistability) and kinetic (rates of system activation and deactivation) response properties. Our integrated computational and synthetic biology approach elucidates design rules for building cellular switches with desired properties, which may be of utility in engineering signal-transduction pathways.
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104-6321, USA.
authors: Santhosh
authors: S
authors: Palani
authors: Casim A
authors: CA
authors: Sarkar
mesh_terms: D017360:Arabidopsis; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli; D025461:Feedback, Physiological; D005453:Fluorescence; D015870:Gene Expression; D053263:Gene Regulatory Networks; D005818:Genetic Engineering / Q000379:methods*; D008024:Ligands; D008957:Models, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012107:Research Design; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058615:Synthetic Biology / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014170:Transformation, Genetic
chemical_list: D029681:Arabidopsis Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C083962:SKN7 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C421783:WOL protein, Arabidopsis