How the Drosophila Cryptochrome C-terminus mediates magnetosensitivity

The Earth’s magnetic field plays an important role in the seasonal migrations of many species of animals. A Cryptochrome (CRY)-based radical pair mechanism (RPM) has been suggested to underlie the mechanistic basis of animal magnetosensitivity and navigation. The quantum spin state of a radical pair involving flavin adenine dinucleotide (FAD) bound to CRY in the canonical pocket is sensitive to external magnetic fields that can alter the signalling concentration of activated CRY ^1–5 . However, several experimental observations challenge this model including the finding that the C-terminal fragment of Drosophila CRY ( Dm CRY), which lacks any canonical FAD binding pocket, and human CRY2, which lacks affinity for FAD, are sufficient to support magnetosensitivity ^6–9 . Here, we use all-atom molecular dynamic (MD) simulations, alongside in vitro and in vivo analyses to reveal that the C-terminus of Drosophila CRY ( Dm CRY-CT) binds FAD. FAD binding is required for transduction of a magnetic signal within cells, and, in vitro , initiates formation of high molecular weight Dm CRY-CT oligomers, including large insoluble aggregates reminiscent of CRY photobodies observed in plants ^10–14 . These results provide a plausible mechanistic basis for several experimental observations that have reported non-canonical magnetosensitivity in animals.