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ACS Synth Biol. 2017 Jul 21;6(7):1337-1342. doi: 10.1021/acssynbio.6b00370. Epub 2017 Mar 28.

Ultrasensitive Scaffold-Dependent Protease Sensors with Large Dynamic Range.

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Institute for Molecular Biosciences, The University of Queensland , QBP Building 80, St Lucia, Queensland 4072, Australia.


The rational construction of synthetic protein switches with predefined input-output parameters constitutes a key goal of synthetic biology with many potential applications ranging from metabolic engineering to diagnostics. Yet, generally applicable strategies to construct tailor-engineered protein switches have so far remained elusive. Here, we use SpyTag/SpyCatcher-mediated protein ligation to engineer modularly organized, scaffold-dependent protease sensors that exploit a combination of affinity targeting and protease-inducible protein-protein interactions. We use this architecture to create a suite of integrated signal sensing and amplification circuits that can detect the activity of α-thrombin and prostate specific antigen with a dynamic range covering 5 orders of magnitude. We determine the key design features critical for signal transmission between protease-based sensors, transducers, and actuators.


molecular diagnostics; proteases; protein engineering; protein switches; synthetic biology

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