The cryptochromes

Abstract

Cryptochromes are photoreceptors that regulate entrainment by light of the circadian clock in plants and animals. They also act as integral parts of the central circadian oscillator in animal brains and as receptors controlling photomorphogenesis in response to blue or ultraviolet (UV-A) light in plants. Cryptochromes are probably the evolutionary descendents of DNA photolyases, which are light-activated DNA-repair enzymes, and are classified into three groups -- plant cryptochromes, animal cryptochromes, and CRY-DASH proteins. Cryptochromes and photolyases have similar three-dimensional structures, characterized by an alpha/beta domain and a helical domain. The structure also includes a chromophore, flavin adenine dinucleotide (FAD). The FAD-access cavity of the helical domain is the catalytic site of photolyases, and it is predicted also to be important in the mechanism of cryptochromes.

Figure 1

An unrooted phylogenetic tree of the photolyase/cryptochrome superfamily, with subfamilies indicated on the right. Abbreviations: A, archaea; B, bacteria; F, fungi I; insects; P, plants; S, sponges; V, vertebrates.

Figure 2

The structure of cryptochromes. A comparison of the structures of the photolyase-related (PHR) regions of (a) Arabidopsis CRY1 and (b) E. coli DNA photolyase. White lines indicate the boundaries of the FAD-access cavity; red and blue represent areas of negative and positive electrostatic potential, respectively. Reproduced with permission from [15]; copyright 2004 National Academy of Sciences USA. (c) A schematic representation of a typical photolyase/cryptochrome superfamily protein. The parts of the PHR region bound by pterin and FAD are indicated with brackets and the domains are shown below the protein. (d) The overall fold of a CRY-DASH protein (Synechosystis sp. PCC6803 cryptochrome).

Figure 3

Regulation of the circadian clock by animal cryptochromes. (a) In Drosophila, Cry suppresses the negative feedback loop of the circadian clock by binding to Tim in a light-dependent manner; this results in the proteosome-dependent ubiquitin-mediated degradation of Tim (Ubq, ubiquitination) and thus to inhibition of the action of the Per-Tim heterodimer. Without Cry, the Per-Tim heterodimer would enter the nucleus and inhibit the binding of clock-cycle proteins (Per, Clk and Bmal1) to the E-box in the promoters of clock genes, preventing their expression. (b) In mammals, cryptochromes are integral parts of the negative feedback loop. The Cry protein interacts with Per to repress the activity of the transcription factors Clk and Bmal1 and thus to repress transcription. Cryptochromes may also be involved in the photo-entrainment of the mammalian circadian clock; clock genes are known to be regulated in response to neural signals from the retina in response to light, but it is not yet clear whether this involves cryptochromes.

Figure 4

Possible models of the phosphorylation-dependent structural changes of plant cryptochromes in response to blue light. The PHR region is predominantly negatively charged (-), and the carboxy-terminal domain (C) can be made negatively charged by phosphorylation (which requires ATP and releases inorganic phosphate, P_i). In all models, phosphorylation leads to binding of unknown signaling partners (X, Y, Z) and to regulation of plant development. (a) One model is that phosphorylation of the carboxy-terminal domain in response to light is performed by ATP bound to the PHR region; this leads to dissociation of the two domains. (b) A second possibility is that phosphotransfer in response to light involves the interaction of two cryptochromes encoded by the same gene. (c) Alternatively, intermolecular phosphotransfer could involve the interaction of different cryptochromes. All three scenarios may exist in plant cells, and the activity of a cryptochrome may be determined by the kinetics of the different reactions.