Interplay of Light, Redox Potential and Temperature in Light-Oxygen-Voltage Receptors

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Sensory photoreceptors endow organisms with sensitivity to light, and they double as genetically encodable actuators in optogenetics for the precise control by light of cellular physiology. Light-oxygen-voltage (LOV) photoreceptors absorb blue light by flavin nucleotides to trigger a canonical photocycle which entails formation of a thioether bond between a strictly conserved cysteine residue and the flavin chromophore. Lacking this cysteine, LOV receptors exhibit enhanced fluorescence and generation of reactive oxygen species (ROS); unexpectedly, cysteine-devoid LOV receptors are capable of downstream signal transduction via blue-light-induced formation of a flavin neutral sem-iquinone radical state. Against this backdrop, we will elucidate the interplay of various inputs (light, temperature and redox potential) and outputs (fluorescence, ROS production, signal transduction) in both cysteine-containing and cysteine-free LOV receptors. Spectroelectrochemical, biochemical and structural analyses will identify molecular determinants governing these processes, in turn allowing the rational construction of enhanced receptors with optimized signal response and minimized side reactivity. By grafting sensitivity to signals other than light onto LOV receptors, novel, precisely con-trollable cellular circuits can be devised. The natural repertoire of proteins comprises multiple entries with significant homology to LOV receptors but lacking one or several normally conserved residues. Mechanistic insight stemming from an in-depth characterization of these putative receptors will fur-ther our understanding of the increasingly multi-facetted roles of LOV receptors in Nature and stand to provide blueprints for the engineering of enhanced derivative receptors sensitive to light, redox potential and/or temperature.