A Novel Signal Transduction Mechanism in Lov Domain Proteins

In light-oxygen-voltage (LOV) domain photoreceptors, blue light irradiation leads to thioether bond formation between the C4a carbon of the flavin-cofactor isoalloxazine ring and a conserved cysteine residue. Adduct formation results in N5 nitrogen protonation and changes in the hydrogen bond network surrounding the cofactor, instigating protein conformational changes and downstream signaling. Interestingly, when the circadian-clock LOV-protein Vivid from Neurospora crassa is devoid of the adduct-forming cysteine, the neutral semiquinone forms upon photoreduction of the cofactor. This variant is surprisingly still capable of dimerization and in vivo signaling. Moreover, analogous LOV domains of natural cysteine-less proteins were discovered to exhibit conformational changes after either chemical reduction or photoreduction. As flavin N5 protonation is a shared event in both the formations of the adduct and the neutral semiquinone, our findings indicate that 1) the neutral semiquinone is a biologically functional state in LOV-proteins and 2) flavin N5 protonation is sufficient for triggering signal transduction.