StaPLs: versatile genetically encoded modules for engineering drug-inducible proteins

Robust approaches for chemogenetic control of protein function would have many biological applications. We developed stabilizable polypeptide linkages (StaPLs) based on hepatitis C virus protease. StaPLs undergo autoproteolysis to cleave proteins by default, whereas protease inhibitors prevent cleavage and preserve protein function. We created StaPLs responsive to different clinically approved drugs to bidirectionally control transcription with zinc-finger-based effectors, and used StaPLs to create single-chain, drug-stabilizable variants of CRISPR–Cas9 and caspase-9. Stabilizable polypeptide linkages (StaPLs) based on hepatitis C virus protease enable robust, reversible, and orthogonal chemogenetic control of protein functions, including CRISPR–Cas9 activity, transcription, and protein dimerization.