Photoactivation of cryptochrome through sequential conformational transitions.

Cryptochromes are blue-light photoreceptor proteins, which provide input to circadian clocks. The cryptochrome from (Cry) modulates the degradation of Timeless and itself. It is unclear how light absorption by the chromophore and the subsequent redox reactions trigger these events. Here, we use nano- to millisecond time-resolved x-ray solution scattering to reveal the light-activated conformational changes in Cry and the related (6-4) photolyase. Cry undergoes a series of structural changes, culminating in the release of the carboxyl-terminal tail (CTT). The photolyase has a simpler structural response. We find that the CTT release in Cry depends on pH. Mutation of a conserved histidine, important for the biochemical activity of Cry, does not affect transduction of the structural signal to the CTT. Instead, molecular dynamics simulations suggest that it stabilizes the CTT in the resting-state conformation. Our structural photocycle unravels the first molecular events of signal transduction in an animal cryptochrome.