Rewiring protein function through genetically encoded oxidative chemistry.

Oxidative chemistry underlies many natural signaling pathways but remains largely unexplored as a design strategy for synthetic control of protein function. Here we introduce genetically encoded oxidative modulation as a general mechanism for regulating protein activity in living cells. Using the genetically encodable photosensitizer miniSOG to generate reactive oxygen species (ROS), we show that controlled oxidation alters the behavior of diverse proteins. miniSOG-derived ROS increased the fluorescence of the redox reporter HyPerRed and activated redox-sensitive ion channels TRPV1 and TRPA1, with TRPA1 displaying the strongest response. The magnitude and kinetics were tunable by illumination parameters, expression ratios, and subcellular localization of miniSOG, with membrane anchoring markedly improving efficiency of activating a membrane receptor. These findings establish genetically encoded oxidative chemistry as a versatile and tunable modality for controlling protein function.