biostudies-literatureUnknown9(1)Landry BPTwo-component systems (TCSs) are the largest family of multi-step signal transduction pathways in biology, and a major source of sensors for biotechnology. However, the input concentrations to which biosensors respond are often mismatched with application requirements. Here, we utilize a mathematical model to show that TCS detection thresholds increase with the phosphatase activity of the sensor histidine kinase. We experimentally validate this result in engineered Bacillus subtilis nitrate and E. coli aspartate TCS sensors by tuning their detection threshold up to two orders of magnitude. We go on to apply our TCS tuning method to recently described tetrathionate and thiosulfate sensors by mutating a widely conserved residue previously shown to impact phosphatase activity. Finally, we appNature communications1433https://www.ebi.ac.uk/biostudies/studies/S-EPMC5897336biostudies-literaturePhosphatase activity tunes two-component system sensor detection threshold.PMC5897336Tabor JJPalanki RHartsough LADyulgyarov NLandry BPfalsePhosphatase activity tunes two-component system sensor detection threshold.Two-component systems (TCSs) are the largest family of multi-step signal transduction pathways in biology, and a major source of sensors for biotechnology. However, the input concentrations to which biosensors respond are often mismatched with application requirements. Here, we utilize a mathematical model to show that TCS detection thresholds increase with the phosphatase activity of the sensor histidine kinase. We experimentally validate this result in engineered Bacillus subtilis nitrate and E. coli aspartate TCS sensors by tuning their detection threshold up to two orders of magnitude. We go on to apply our TCS tuning method to recently described tetrathionate and thiosulfate sensors by mutating a widely conserved residue previously shown to impact phosphatase activity. Finally, we app2018-01-01T00:00:00Z2018 Apr2025-04-18T18:22:09.787Z2019-03-26T23:29:33ZS-EPMC58973362965095810.1038/s41467-018-03929-y