An international research team led by Professor Manuel Maestre-Reyna from National Taiwan University has filmed a high-resolution, 3D molecular movie of a cryptochrome in action. The work is published in the journal Science Advances.
Cryptochromes are light-sensitive proteins found in most living things, including plants and animals. They help keep time with day and night by controlling internal clocks and responses to light. They are important for things like sleep cycles, plant growth, and possibly even sensing Earth's magnetic field.
Until now, scientists knew that cryptochromes function by absorbing blue light, which triggers structural changes in the protein. This activates interactions with other cellular proteins, influencing gene expression and biological rhythms. However, the mechanism by which cryptochromes manifest this light-sensing ability had remained unclear.
To achieve the high-resolution, 3D molecular movie of a cryptochrome in action, the team used time-resolved serial femtosecond crystallography (TR-SFX) at Spring-8 Angstrom Compact X-ray Free Electron Laser (SACLA) in Japan initially. They collected 19 individual "frames" spanning from 10 nanoseconds to 233 milliseconds after illumination to put together the final movie.
The resulting ultra-slow motion, atomic resolution film explains how the cryptochrome protein amplifies the subtle photochemical signal, which then snowballs into dramatic structural changes. The process is coordinated by the protein, with three molecular regions acting in unison to accomplish sensing.
First, during the initial photochemical change, flavin adenine dinucleotide (FAD), a special light-gathering moiety within the protein, used the energy of blue light to capture an electron from the cryptochrome itself, inducing a highly unstable radical pair state.
Within nanoseconds, the protein attempts to stabilize this short-lived species by modulating its immediate environment. These local changes cascade over time, until, by about 100 milliseconds after RP formation, entire regions of the protein unfold like a ribbon, signaling that cryptochrome has sensed light.
In addition, because transient formation of radical pairs similar to those found in the cryptochrome photocycle also take part in energy production in cells, photosynthesis, and even magnetic field sensing by living beings. Thus, the cryptochrome molecular mechanism may act as a model system to better understand the fundamentals of these wide-ranging topics.
"With time-resolved crystallography, we have ensued in an age of protein movie making, giving unprecedented insight into the chemical principles of light-triggered processes in nature," said Prof. Maestre-Reyna. "I am happy to represent the NTU at the forefront of this scientific frontier."
More information: Manuel Maestre-Reyna et al, Capturing structural intermediates in an animal-like cryptochrome photoreceptor by time-resolved crystallography, Science Advances (2025). DOI: 10.1126/sciadv.adu7247
Journal information: Science Advances
Provided by National Taiwan University