Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

Abstract

Birds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in a model of the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an -helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation communities, which facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues characterized by high betweenness centrality. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

The sacrificial inactivation of the blue-light photosensor cryptochrome from Drosophila melanogaster

“…S21, ESI†) accompanied by Trp decomposition and allowing FAD release. Consistent with our suggestion, in previous studies it was shown that absorption of light by DmCRY leads to conformational changes in the CTT, that were shown to be largely irreversible,49–51 thus allowing the interaction with TIM followed by proteasomal degradation of both proteins. Further, we suggest that similar to animal type II CRY,53 the E3 ubiquitin ligase, Ramshackle,13 binds to the DmCRY FAD-binding pocket making the FAD release a requirement for subsequent ubiquitylation and its proteasomal degradation, thus, allowing the next cycle of the circadian clock (Fig.…”

Chemical and structural analysis of a photoactive vertebrate cryptochrome from pigeon

“…Notably, the nature of the involvement of the CTT diverges in the type IV CRYs, where an increase in proteolysis is not observed and the CTT rather may be protected in the light. Furthermore, in contrast to recent molecular dynamics simulations of Cl CRY4, crystal structures of WT and Y319D PHR domains confirm that His353 contacts the ribityl chain of FAD to enable type I-like protonation events to affect contacts to the CTT in the ground and/or signaling states (45, 53). Thus, based on limited proteolysis assays, the primary photochemical events mirror type I CRYs, in which initial formation of the semiquinone state of FAD could propagate to the FAD-binding cleft to alter the protonation state of a conserved His residue.…”

Protein-protein interaction of the putative magnetoreceptor cryptochrome 4 expressed in the avian retina

“…The direction of the magnetic field influences, how much of the Cry goes back to the ground state and how much of the Cry is converted to a signalling state. This process probably leads to a conformational change in the C-terminus of Cry4 that is also observed in other Cry variants 18,20,[27][28][29] . This photo-excited Cry would then trigger a magneto-sensitive cell response via protein-protein interactions.…”