Light-induced conformational switching and magnetic sensitivity of Drosophila cryptochrome

Cryptochromes are flavoproteins with a number of established and proposed biological functions based on their sensitivity to light. Amongst the latter is the possibility that cryptochromes mediate the geomagnetic compass sense used by migratory birds as a navigational cue. This hypothesis rests on a magnetically sensitive photochemical reaction of the flavin chromophore in which a series of electron transfers within the protein scaffold ultimately generates a signal propagated within the central nervous system of the animal. Although there is a good understanding of the photochemistry and the electron transfer pathway, the protein-mediated mechanisms of signal transduction are still unclear. Here we have examined the response of Drosophila melanogaster cryptochrome - DmCRY, an archetypal cryptochrome - to photochemical activation by means of molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and cavity ring-down spectroscopy. We were able to measure the dynamics of DmCRY at near-residue level resolution, revealing a reversible, long-lived, blue-light induced conformational change in the C-terminal tail of the protein. This putative signalling state was validated using different illumination conditions, and by examining DmCRY variants in which the electron transfer chain was disrupted by point mutation. Our results show how the photochemical behaviour of the flavin chromophore generates a state of DmCRY that may act as a key primer for modulating downstream interactions.