Light–oxygen–voltage (LOV) receptors sense blue light through the
photochemical generation of a covalent adduct between a flavin-nucleotide
chromophore and a strictly conserved cysteine residue. Here we show that,
after cysteine removal, the circadian-clock LOV-protein Vivid still undergoes
light-induced dimerization and signalling because of flavin photoreduction to
the neutral semiquinone (NSQ). Similarly, photoreduction of the engineered LOV
histidine kinase YF1 to the NSQ modulates activity and downstream effects on
gene expression. Signal transduction in both proteins hence hinges on flavin
protonation, which is common to both the cysteinyl adduct and the NSQ. This
general mechanism is also conserved by natural cysteine-less, LOV-like
regulators that respond to chemical or photoreduction of their flavin
cofactors. As LOV proteins can react to light even when devoid of the adduct-
forming cysteine, modern LOV photoreceptors may have arisen from ancestral
redox-active flavoproteins. The ability to tune LOV reactivity through
photoreduction may have important implications for LOV mechanism and
optogenetic applications