Synthetic protein switches: design principles and applications

•Engineered protein switches are increasingly used in molecular diagnostics.•Engineered protein switches can be used to sense and actuate cellular functions.•Empirical design rules to construct tailor-engineered protein switches are emerging.•Future synthetic signaling circuits will see networks of engineered protein switches.

Protein switches are ubiquitous in biological signal transduction systems, enabling cells to sense and respond to a variety of molecular queues in a rapid, specific, and integrated fashion. Analogously, tailor-engineered protein switches with custom input and output functions have become invaluable research tools for reporting on distinct physiological states and actuating molecular functions in real time and in situ. Here, we analyze recent progress in constructing protein-based switches while assessing their potential in the assembly of defined signaling motifs. We anticipate such systems will ultimately pave the way towards a new generation of molecular diagnostics and facilitate the construction of artificial signaling systems that operate in parallel to the signaling machinery of a host cell for applications in synthetic biology.