Wikipedia

Cryptochrome

Cryptochromes(from theGreekκρυπτός χρώμα, "hidden colour" ) are a class offlavoproteinsfound inplantsandanimalsthat are sensitive toblue light.They are involved in thecircadian rhythmsand thesensing of magnetic fieldsin a number of species. The namecryptochromewas proposed as aportmanteaucombining thechromaticnature of thephotoreceptor,and thecryptogamicorganisms on which many blue-light studies were carried out.[1][2]

Cryptochrome-1
Crystallographic structure of Cryptochrome-1
Identifiers
SymbolCRY1
NCBI gene1407
HGNC2384
OMIM601933
PDB5T5X
RefSeqNP_004066
UniProtQ16526
Other data
LocusChr. 12q23.3
Search for
StructuresSwiss-model
DomainsInterPro

Cryptochrome-2
Identifiers
SymbolCRY2
NCBI gene1408
HGNC2385
OMIM603732
PDB4MLP
RefSeqNP_066940
UniProtQ49AN0
Other data
LocusChr. 11p11.2
Search for
StructuresSwiss-model
DomainsInterPro
"CRY1" redirects here. For other uses, seeCRY1 (disambiguation).

ThegenesCRY1andCRY2encode theproteinsCRY1 and CRY2, respectively.[3]Cryptochromes are classified into plant Cry and animal Cry. Animal Cry can be further categorized into insect type (Type I) and mammal-like (Type II). CRY1 is a circadianphotoreceptorwhereas CRY2 is a clockrepressorwhich represses Clock/Cycle (Bmal1) complex in insects andvertebrates.[4]In plants, blue-light photoreception can be used to cue developmental signals.[5]Besideschlorophylls,cryptochromes are the only proteins known to form photoinducedradical-pairsin vivo.[6]These appear to enable some animals to detect magnetic fields.

Cryptochromes have been the focus of several current efforts inoptogenetics.Employingtransfection,initial studies on yeast have capitalized on the potential of CRY2heterodimerizationto control cellular processes, includinggene expression,by light.

Discovery

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AlthoughCharles Darwinfirst documented plant responses to blue light in the 1880s, it was not until the 1980s that research began to identify the pigment responsible.[7]In 1980, researchers discovered that the HY4 gene of the plantArabidopsis thalianawas necessary for the plant's blue light sensitivity, and, when the gene was sequenced in 1993, it showed high sequence homology withphotolyase,a DNA repair protein activated by blue light.[8]Reference sequence analysis of cryptochrome-1 isoform d shows twoconserveddomains with photolyase proteins. Isoform d nucleotide positions 6 through 491 show a conserved domain withdeoxyribodipyrimidine photolyase,and positions 288 through 486 show a conserved domain with the FAD binding domain of DNA photolyase.[9]Comparative genomic analysis supports photolyase proteins as the ancestors of cryptochromes. However, by 1995 it became clear that the products of the HY4 gene and its two humanhomologsdid not exhibit photolyase activity and were instead a new class ofblue lightphotoreceptor hypothesized to becircadianphotopigments.[10]In 1996 and 1998,Cryhomologs were identified inDrosophilaandmice,respectively.[11][12]

Evolutionary history

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Cryptochromes (CRY1, CRY2) are evolutionarily old and highly conserved proteins that belong to the flavoproteins superfamily that exists in all kingdoms of life. Cryptochromes are derived from and closely related to photolyases, which are bacterialenzymesthat are activated by light and involved in the repair of UV-inducedDNA damage.

Ineukaryotes,cryptochromes no longer retain this original enzymatic activity. By using aT-DNAlabeled allele of thecry1gene in theArabidopsisplant, researchers determined that thecry1gene encoded a flavoprotein without photolyase activity and with a uniqueC-terminal tail.[13]The protein encoded by this gene was named cryptochrome 1 to distinguish it from its ancestral photolyase proteins and was found to be involved in the photoreception of blue light. Studies ofDrosophila cry-knockout mutants led to the later discovery that cryptochrome proteins are also involved in regulating the mammalian circadian clock. TheDrosophila crygene similarly encodes a flavoprotein without photolyase activity that also bindspterinchromophores.[13]Crymutants (cryb)were found to express arrhythmic levels ofluciferaseas well asPERandTIMproteins in photoreceptor cells.[13]Despite the arrhythmicity of these protein levels,crybmutants still showed rhythmicity in overall behavior but could notentrainto short pulses of light, leading researchers to conclude that the dorsal and ventral lateral neurons (the primarypacemaker cellsofDrosophila)were still functioning effectively.[13]Whencrybmutants also had visually unresponsive compound eyes, though, they failed to behaviorally entrain toenvironmental cues.[13]These findings led researchers to conclude that the cryptochrome protein encoded bycryis necessary forDrosophilaphotoentrainment. In mammals, a protein analog of theDrosophilacryptochrome protein was discovered with the characteristic property of lacking photolyase activity, prompting researchers to consider it in the same class of cryptochrome proteins.[13]In mice, the greatestcry1expression is observed in thesuprachiasmatic nucleus(SCN) where levels rhythmically fluctuate.[13]Due to the role of the SCN as the primary mammalian pacemaker as well as the rhythmic fluctuations incry1expression, researchers concludedcry1was also necessary for the entrainment of mammalian circadian rhythms.

A common misconception in the evolutionary history of cryptochrome proteins is that mammalian and plant proteins areorthologsof each other that evolved directly from a shared photolyase gene. However, genomic analysis indicates that mammalian and fly cryptochrome proteins show greatersequence similarityto the (6-4) photolyase proteins than to plant cryptochrome proteins.[13]It is therefore likely that plant and animal cryptochrome proteins show a unique case ofconvergent evolutionby repeatedly evolving new functions independently of each other from a single common ancestralcrygene.[13]

Research by Worthington et al. (2003) indicates that cryptochromes first evolved in bacteria and were identified inVibrio cholerae.[14]Genome sequencing of this bacteria identified three genes in the photolyase/cryptochrome family, all of which have thefolateandflavincofactors characteristic of these proteins.[14]Of these genes, one encodes a photolyase, while the other two encode cryptochrome proteins designated VcCry1 and VcCry2.[14]Cashmore AR et al. (1999) hypothesize that mammalian cryptochromes developed later in evolutionary history shortly after plants and animals diverged based on conserved genomic domains between animal cryptochromes and theArabidopsis(6-4) photolyase protein.[13]Based on the role of cryptochromes in the entrainment of mammalian circadian rhythms, current researchers hypothesize that they developed simultaneously with the coevolution of PER, TIM,CLOCK,andCYCLEproteins, but there is currently insufficient evidence to determine the exact evolution timing and mechanism of evolution.[13]

Structure

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All members of the flavoprotein superfamily have the characteristics of anN-terminalphotolyase homology(PHR) domain. The PHR domain can bind to theflavin adenine dinucleotide(FAD)cofactorand alight-harvestingchromophore.[15]The structure of cryptochrome involves a fold very similar to that of photolyase, arranged as an orthogonal bundle with a single molecule of FADnoncovalentlybound to the protein.[15]These proteins have variable lengths and surfaces on the C-terminal end, due to the changes in genome and appearance that result from the lack ofDNA repair enzymes.[15]TheRamachandran plotshows that thesecondary structureof the CRY1 protein is primarily a right-handedAlpha helixwith little to no steric overlap. The structure of CRY1 is almost entirely made up of Alpha helices, with several loops and fewbeta sheets.[15]

Function

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Phototropism

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In plants, cryptochromes mediatephototropism,or directional growth toward a light source, in response to blue light. This response is now known to have its own set of photoreceptors, thephototropins.

Unlikephytochromesand phototropins, cryptochromes are notkinases.Theirflavinchromophoreis reduced by light and transported into thecell nucleus,where it affects theturgor pressureand causes subsequent stem elongation. To be specific,Cry2is responsible for blue-light-mediatedcotyledonand leaf expansion.Cry2overexpression intransgenicplants increases blue-light-stimulated cotyledon expansion, which results in many broad leaves and no flowers rather than a few primary leaves with a flower.[16]A double loss-of-function mutation in Arabidopsis thaliana Early Flowering 3 (elf3) and Cry2 genes delays flowering under continuous light and was shown to accelerate it during long and short days, which suggests that Arabidopsis CRY2 may play a role in accelerating flowering time during continuous light.[17]

Photomorphogenesis

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Cryptochromes receptors cause plants to respond to blue light viaphotomorphogenesis.They help control seed and seedling development, as well as the switch from the vegetative to the flowering stage of development.

InArabidopsis,CRY1 is the primary inhibitor of hypocotyl elongation but CRY2 inhibits hypocotyl elongation under low blue light intensity. CRY2 promotes flowering under long-day conditions.[18]

CRY gene mediates photomorphogenesis in several ways. CRY C-terminal interacts with CONTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a E3 ubiquitin ligase that represses photomorphogenesis and flowering time. The interaction inhibits COP1 activity and allows transcription factors such as ELONGATED HYPOCOTYL 5 (HY5) to accumulate.[19]HY5 is a basic leucine zipper (bZIP) factor that promotes photomorphogenesis by binding to light-responsive genes. CRY interacts with G protein β-subunit AGB1, where HY5 dissociates from AGB1 and becomes activated. CRY interacts with PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) and PIF5, repressors of photomorphogenesis and promoter of hypocotyl elongation, to repress PIF4 and PIF5 transcription activity. Lastly, CRY can inhibitauxinandbrassinosterioid(BR) signaling to promote photomorphogenesis.[18]

Light capture

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Despite much research on the topic, cryptochromephotoreceptionandphototransductioninDrosophilaandArabidopsis thalianais still poorly understood. Cryptochromes are known to possess two chromophores:pterin(in the form of5,10-methenyltetrahydrofolic acid(MTHF)) and flavin (in the form of FAD).[20]Both may absorb aphoton,and inArabidopsis,pterin appears to absorb at a wavelength of 380 nm and flavin at 450 nm. Past studies have supported a model by which energy captured by pterin is transferred to flavin.[21]Under this model of phototransduction, FAD would then bereducedto FADH, which probably mediates thephosphorylationof a certain domain in cryptochrome. This could then trigger asignal transductionchain, possibly affectinggene regulationin thecell nucleus.

A new hypothesis[22]proposes that partner molecules sense the transduction of a light signal into a chemical signal in plant cryptochromes, which could be triggered by a photo-induced negative charge on the FAD cofactor or on the neighboring aspartic acid[23][24]within the protein. This negative charge would electrostatically repel the protein-boundATPmolecule and thereby also the protein C-terminal domain, which covers theATPbinding pocket prior to photon absorption. The resulting change in protein conformation could lead to phosphorylation of previously inaccessible phosphorylation sites on the C-terminus and the given phosphorylated segment could then liberate the transcription factor HY5 by competing for the same binding site at the negative regulator of photomorphogenesisCOP1.

A different mechanism may function inDrosophila.The true ground state of the flavin cofactor inDrosophilaCRY is still debated, with some models indicating that the FAD is in an oxidized form,[25]while others support a model in which the flavin cofactor exists inanionradicalform,FAD−
•. Recently, researchers have observed that oxidized FAD is readily reduced toFAD−
• by light. Furthermore, mutations that blocked photoreduction had no effect on light-induced degradation of CRY, while mutations that altered the stability ofFAD−
• destroyed CRY photoreceptor function.[26][27]These observations provide support for a ground state ofFAD−
•. Researchers have also recently proposed a model in whichFAD−
is excited to itsdoubletor quartet state by absorption of a photon, which then leads to a conformational change in the CRY protein.[28]

Also the ring eyes of thedemospongelarva ofAmphimedon queenslandicaexpress a blue-light-sensitive cryptochrome (Aq-Cry2), which might mediate phototaxis. In contrast, the eyes of most animals usephoto-sensitiveopsinsexpressed in photoreceptor cells, which communicate information about light from the environment to the nervous system. However,A. queenslandicalacks a nervous system, like othersponges.And it does not have anopsingenein its fully sequencedgenomeeither, despite having many otherG-protein-coupled receptors(GPCRs). Therefore, the sponge's unique eyes must have evolved a different mechanism to detect light and mediate phototaxis, possibly with cryptochromes or other proteins.[29]

Iris function

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Isolated irises constrict in response to light via a photomechanical transduction response (PMTR) in a variety of species and require eithermelanopsinor cryptochrome to do so.[30]The iris of chicken embryos senses short-wavelength light via a cryptochrome, rather than opsins.[31]Research by Margiotta and Howard (2020) shows that the PMTR of the chicken iris striated muscle occurs withCRYgene activation by 430 nm blue light.[30]The PMTR was inhibited inCRYgene knockouts and decreased when flavin reductase was inhibited, but remained intact with the addition of melanopsin antagonists.[30]Similarly, cytosolicCRY1andCRY2proteins were found in irismyotubes,and decreasing transcription of these genes inhibited PMTRs.[30]The greatest iris PMTRs therefore correspond with the development of striated, rather than smooth, muscle fibers throughCRY-mediated PMTRs.[30]

Circadian rhythm

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Studies in animals and plants suggest that cryptochromes play a pivotal role in the generation and maintenance of circadian rhythms.[32]Similarly, cryptochromes play an important role in the entrainment of circadian rhythms in plants.[33]InDrosophila,cryptochrome (dCRY) acts as a blue-light photoreceptor that directly modulates light input into the circadian clock,[34]while in mammals, cryptochromes (CRY1 and CRY2) act astranscriptionrepressorswithin the circadian clockwork.[35]Some insects, including themonarch butterfly,have both a mammal-like and aDrosophila-like version of cryptochrome, providing evidence for an ancestral clock mechanism involving both light-sensing and transcriptional-repression roles for cryptochrome.[36][37]

Crymutantshave altered circadian rhythms, showing thatCryaffects the circadian pacemaker.Drosophilawith mutatedCryexhibit little to no mRNA cycling.[38]A point mutation incryb,which is required for flavin association in CRY protein, results in no PER or TIM protein cycling in either DD or LD.[39]In addition, mice lackingCry1orCry2genes exhibit differentially altered free running periods, but are still capable ofphotoentrainment.However, mice that lack bothCry1andCry2are arrhythmic in both LD and DD and always have highPer1mRNA levels. These results suggest that cryptochromes play a photoreceptive role, as well as acting as negative regulators of Per gene expression in mice.[40]

InDrosophila

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InDrosophila,cryptochrome is only encoded by oneCrygene (dCry)and functions as a blue light photoreceptor. Exposure to blue light induces a conformation similar to that of the always-active CRY mutant with a C-terminal deletion (CRYΔ).[28]The half-life of this conformation is 15 minutes in the dark and facilitates the binding of CRY to other clock gene products, PER andTIM,in a light-dependent manner.[41][28][34][42]Once bound by dCRY, dTIM is committed to degradation by the ubiquitin-proteasomesystem.[28][42]

Although light pulses do not entrain, full photoperiod LD cycles can still drive cycling in theventral-lateralneurons in theDrosophilabrain. These data along with other results suggest that CRY is the cell-autonomous photoreceptor for body clocks inDrosophilaand may play a role in nonparametric entrainment (entrainment by short discrete light pulses). However, the lateral neurons receive light information through both the blue light CRY pathway and therhodopsinpathway. Therefore, CRY is involved in light perception and is an input to the circadian clock, however it is not the only input for light information, as a sustained rhythm has been shown in the absence of the CRY pathway, in which it is believed that the rhodopsin pathway is providing some light input.[43]Recently, it has also been shown that there is a CRY-mediated light response that is independent of the classical circadian CRY-TIM interaction. This mechanism is believed to require a flavinredox-based mechanism that is dependent on potassium channel conductance. This CRY-mediated light response has been shown to increaseaction potentialfiring within seconds of a light response inopsin-knockoutDrosophila.[44]

Cryptochrome, like many genes involved in circadian rhythm, shows circadian cycling inmRNAand protein levels. InDrosophila,CrymRNA concentrations cycle under a light-dark cycle (LD), with high levels in light and low levels in the dark.[38]This cycling persists in constant darkness (DD), but with decreased amplitude.[38]The transcription of theCrygene also cycles with a similar trend.[38]CRY protein levels, however, cycle in a different manner thanCrytranscription and mRNA levels. In LD, CRY protein has low levels in light and high levels in dark, and, in DD, CRY levels increase continuously throughout the subjective day and night.[38]Thus, CRY expression is regulated by the clock at the transcriptional level and by light at thetranslationaland posttranslational level.[38]

Overexpression ofCryalso affects circadian light responses. InDrosophila,Cryoverexpression increases flies' sensitivity to low-intensity light.[38]This light regulation of CRY protein levels suggests that CRY has a circadian role upstream of other clock genes and components.[38]

In mammals

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In mammals, cryptochrome proteins are encoded by two genes,Cry1andCry2.

Cry2
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Cryptochrome is one of the four groups of mammalian clock genes/proteins that generate a transcription-translation negative-feedback loop (TTFL), along withPeriod (PER),CLOCK,andBMAL1.[45]In this loop, CLOCK and BMAL1 proteins aretranscriptional activators,which together bind to thepromotersof theCry2andPergenes and activate their transcription.[45]The CRY2 and PER proteins then bind to each other, enter the nucleus, and inhibit CLOCK-BMAL1-activated transcription.[45]The overall function of CRY2 is therefore to repress transcription of CLOCK and BMAL1.

Cry1
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Cry1encodes the CRY1 protein which is a mammalian circadian photoreceptor. In mice,Cry1expression displays circadian rhythms in thesuprachiasmatic nucleus,a brain region involved in the generation of circadian rhythms, with mRNA levels peaking during the light phase and reaching a minimum in the dark.[46]These daily oscillations in expression are maintained in constant darkness.[46]

While CRY1 has been well established as a TIM homolog in mammals, the role of CRY1 as a photoreceptor in mammals has been controversial. Early papers indicated that CRY1 has both light-independent and -dependent functions. A study conducted by Selby CP et al. (2000) found that mice without rhodopsin but with cryptochrome still respond to light; however, in mice without either rhodopsin or cryptochrome,c-Fostranscription, a mediator of light sensitivity, significantly drops.[47]In recent years, data have supportedmelanopsinas the main circadian photoreceptor, in particular melanopsin cells that mediate entrainment and communication between theeyeand the suprachiasmatic nucleus (SCN).[48]One of the main difficulties in confirming or denying CRY as a mammalian photoreceptor is that when the gene is knocked out the animal goes arrhythmic, so it is hard to measure its capacity as purely a photoreceptor. However, some recent studies indicate that human CRY1 may mediate light response in peripheral tissues.[49]

Normal mammalian circadian rhythm relies critically on delayed expression ofCry1following activation of theCry1promoter. Whereas rhythms inPer2promoter activation andPer2mRNA levels have almost the same phase,Cry1mRNA production is delayed by approximately four hours relative toCry1promoter activation.[50]This delay is independent of CRY1 or CRY2 levels and is mediated by a combination ofE/E'-boxand D-box elements in the promoter andRevErbA/RORbinding elements (RREs) in the gene's first intron.[51]Transfectionof arrhythmicCry1−/−Cry2−/−double-knockout cells with only theCry1promoter (causing constitutiveCry1expression) is not sufficient to rescue rhythmicity. Transfection of these cells with both the promoter and the firstintronis required for restoration of circadian rhythms in these cells.[51]

There is evidence that CRY1 can play a role in how sleep-wake patterns can beinheritedthrough families. There is a mutation,CRY1Δ11,that causes a delay in one's circadian rhythm.[52]CRY1Δ11 is a splicing variant that has deleted anauto-inhibitorysection of the gene.[52]It causes a delay by increasing the affinity of CLOCK andBMALwhich in turn lengthens the period.[52]This causes people with this mutation to have a later sleep midpoint than the rest of the population, causing a disorder known asdelayed sleep–wake phase disorder.[52]

CRY1 is also a key modulator inDNA repair,specifically through temporal regulation.[53]CRY1 has an impact in the cell cycle progression, particularly in theG2/Mcheckpoint, and thedepletion of CRY1leads to effects on DNA repair networks, including mismatch repair, UV, andnucleotide excision.[53]Incancer,CRY1 is stabilized by DNA damage, which results in CRY1 expression being associated with worse outcomes inprostate cancer.[53]Because of its role in DNA repair and beingpro-tumorigenic,further research can use CRY1 as atherapeutic target.

Variants of CRY1 can have impacts on humans in regards to metabolic output. According to a 2021 study,metabolic outputs,measured bybowel movements,were severely different for participants who werewild typein comparison to those with the CRY1Δ11 variant.[52]The participants with the variant had a delayed sleep cycle anddelayed metabolic outputwhen compared to the wild type.[52]

Magnetoreception

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Main article:Magnetoreception
Theradical pair mechanismhas been proposed for quantum magnetoreception in birds.[54]

Magnetoreception is a sense which allows an organism to detect a magnetic field to perceive direction, altitude or location. Experimental data suggests that cryptochromes in thephotoreceptor neuronsof birds' eyes are involved in magnetic orientation duringmigration.[55]Cryptochromes are also thought to be essential for the light-dependent ability ofDrosophilato sensemagnetic fields.[56]Magnetic fields were once reported to affect cryptochromes also inArabidopsis thalianaplants: growth behavior seemed to be affected by magnetic fields in the presence of blue (but not red) light.[57]Nevertheless, these results have later turned out to be irreproducible under strictly controlled conditions in another laboratory,[58]suggesting that plant cryptochromes do not respond to magnetic fields.

Cryptochrome forms a pair ofradicalswith correlatedspinswhen exposed to blue light.[59][60]Radical pairs can also be generated by the light-independent dark reoxidation of the flavin cofactor by molecular oxygen through the formation of a spin-correlated FADH-superoxide radical pairs.[61]Magnetoreception is hypothesized to function through the surrounding magnetic field's effect on the correlation (parallel or anti-parallel) of these radicals, which affects the lifetime of the activated form of cryptochrome. Activation of cryptochrome may affect the light-sensitivity ofretinalneurons, with the overall result that the animal can sense the magnetic field.[62]Animal cryptochromes and closely related animal (6-4) photolyases contain a longer chain of electron-transferring tryptophans than other proteins of the cryptochrome-photolyase superfamily (a tryptophan tetrad instead of a triad).[63][64]The longer chain leads to a better separation and over 1000× longer lifetimes of the photoinduced flavin-tryptophan radical pairs than in proteins with a triad of tryptophans.[63][64]The absence of spin-selective recombination of these radical pairs on the nanosecond to microsecond timescales seems to be incompatible with the suggestion that magnetoreception by cryptochromes is based on the forward light reaction.

References

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