Cryptochromes (from the

Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group. *Greek language, a branch of the Indo-European language family. **Proto-Greek language, the assumed last common ancestor ...

κρυπτός χρώμα, "hidden colour") are a class of

flavoproteins Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repai ...

found in

plants Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclude ...

and

animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

s that are sensitive to

blue light Blue Light or Blue light may refer to: Science and technology * Portion of the visible spectrum related to the blue color ** Blue laser ** Blue LED * Cherenkov radiation, the physical phenomenon responsible for the characteristic blue glow in nucl ...

. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name ''cryptochrome'' was proposed as a ''

portmanteau A portmanteau word, or portmanteau (, ) is a blend of wordschromatic'' nature of the photoreceptor, and the ''

cryptogam A cryptogam (scientific name Cryptogamae) is a plant (in the wide sense of the word) or a plant-like organism that reproduces by spores, without flowers or seeds. The name ''Cryptogamae'' () means "hidden reproduction", referring to the fact ...

ic'' organisms on which many blue-light studies were carried out. The two

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s ''Cry1'' and ''Cry2'' code the two cryptochrome

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s CRY1 and CRY2. In

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

and plants, CRY1 regulates the circadian clock in a light-dependent fashion, whereas in

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

, CRY1 and CRY2 act as light-independent inhibitors of

CLOCK A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and t ...

BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...

components of the circadian clock. In plants, blue-light photoreception can be used to cue developmental signals. Besides chlorophylls, cryptochromes are the only proteins known to form photoinduced radical-pairs ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

''. These appear to enable some animals to detect magnetic fields. Cryptochromes have been the focus of several current efforts in

optogenetics Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by expression of light-sensitive ion channels, pumps or enzymes specifically in the target cells. On the level of individ ...

. Employing

transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...

, initial studies on yeast have capitalized on the potential of Cry2

heterodimerization In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

to control cellular processes, including gene expression, by light.

Discovery

Although

Charles Darwin Charles Robert Darwin ( ; 12 February 1809 – 19 April 1882) was an English naturalist, geologist, and biologist, widely known for his contributions to evolutionary biology. His proposition that all species of life have descended ...

first documented plant responses to blue light in the 1880s, it was not until the 1980s that research began to identify the pigment responsible. In 1980, researchers discovered that the HY4 gene of the plant '' Arabidopsis thaliana'' was necessary for the plant's blue light sensitivity, and, when the gene was sequenced in 1993, it showed high sequence homology with

photolyase Photolyases () are DNA repair enzymes that repair damage caused by exposure to ultraviolet light. These enzymes require visible light (from the violet/blue end of the spectrum) both for their own activation and for the actual DNA repair. The DN ...

, a DNA repair protein activated by blue light. By 1995, it became clear that the products of the HY4 gene and its two human

homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...

did not exhibit photolyase activity and were instead a new class of

photoreceptor hypothesized to be circadian

photopigment Photopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and pho ...

s. In 1996 and 1998, ''Cry'' homologs were identified in ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

'' and mice, respectively.

Evolutionary history and structure

Cryptochromes (CRY1, CRY2) are evolutionarily old and highly conserved proteins that belong to the flavoproteins superfamily that exists in all kingdoms of life. All members of this superfamily have the characteristics of an N-terminal photolyase homology (PHR) domain. The PHR domain can bind to the flavin adenine dinucleotide (FAD) cofactor and a light-harvesting chromophore. Cryptochromes are derived from and closely related to

s, which are bacterial enzymes that are activated by light and involved in the repair of UV-induced DNA damage. In eukaryotes, cryptochromes no longer retain this original enzymatic activity. The structure of cryptochrome involves a fold very similar to that of photolyase, with a single molecule of FAD noncovalently bound to the protein. 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 of DNA repair enzymes. The

Ramachandran plot In biochemistry, a Ramachandran plot (also known as a Rama plot, a Ramachandran diagram or a �,ψplot), originally developed in 1963 by G. N. Ramachandran, C. Ramakrishnan, and V. Sasisekharan, is a way to visualize energetically allowed regions ...

shows that the secondary structure of the CRY1 protein is primarily a right-handed alpha helix with little to no steric overlap. The structure of CRY1 is almost entirely made up of alpha helices, with several loops and few

beta sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

. The molecule is arranged as an orthogonal bundle.

Function

Phototropism

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

phototropin Phototropins are photoreceptor proteins (more specifically, flavoproteins) that mediate phototropism responses in higher plants. Phototropins can be found throughout the leaves of a plant. Along with cryptochromes and phytochromes they allow plants ...

s. Unlike

phytochrome Phytochromes are a class of photoreceptor in plants, bacteria and fungi used to detect light. They are sensitive to light in the red and far-red region of the visible spectrum and can be classed as either Type I, which are activated by far-re ...

s and phototropins, cryptochromes are not

kinases In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

. Their flavin chromophore is reduced by light and transported into the cell nucleus, where it affects the

turgor pressure Turgor pressure is the force within the cell that pushes the plasma membrane against the cell wall. It is also called ''hydrostatic pressure'', and is defined as the pressure in a fluid measured at a certain point within itself when at equilibriu ...

and causes subsequent stem elongation. To be specific, ''Cry2'' is responsible for blue-light-mediated

cotyledon A cotyledon (; ; ; , gen. (), ) is a significant part of the embryo within the seed of a plant, and is defined as "the embryonic leaf in seed-bearing plants, one or more of which are the first to appear from a germinating seed." The num ...

and leaf expansion. ''Cry2'' overexpression in

transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

plants increases blue-light-stimulated cotyledon expansion, which results in many broad leaves and no flowers rather than a few primary leaves with a flower. 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.

Photomorphogenesis

Cryptochromes receptors cause plants to respond to blue light via photomorphogenesis. They help control seed and seedling development, as well as the switch from the vegetative to the flowering stage of development. In Arabidopsis, it has been shown that cryptochromes controls plant growth during sub-optimal blue-light conditions.

Light capture

Despite much research on the topic, cryptochrome

photoreception A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiatio ...

and phototransduction in ''

'' and ''Arabidopsis thaliana'' is still poorly understood. Cryptochromes are known to possess two chromophores:

pterin Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" (a lactam) and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, ...

(in the form of

5,10-methenyltetrahydrofolic acid 5,10-Methenyltetrahydrofolate (5,10-CH=THF) is a form of tetrahydrofolate that is an intermediate in metabolism. 5,10-CH=THF is a coenzyme that accepts and donates methenyl (CH=) groups. It is produced from 5,10-methylenetetrahydrofolate by eith ...

(MTHF)) and flavin (in the form of FAD). Both may absorb a

photon A photon () is an elementary particle that is a quantum of the electromagnetic field, including electromagnetic radiation such as light and radio waves, and the force carrier for the electromagnetic force. Photons are massless, so they a ...

, and in ''Arabidopsis'', 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. Under this model of phototransduction, FAD would then be reduced to FADH, which probably mediates the phosphorylation of a certain domain in cryptochrome. This could then trigger a signal transduction chain, possibly affecting

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wi ...

in the cell nucleus. A new hypothesis proposes that in plant cryptochromes, the transduction of the light signal into a chemical signal that might be sensed by partner molecules could be triggered by a photo-induced negative charge within the protein - on the FAD cofactor or on the neighbouring aspartic acid. This negative charge would electrostatically repel the protein-bound ATP molecule and thereby also the protein C-terminal domain, which covers the ATP binding 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 photomorphogenesis

COP1 ''For the membrane coated vesicle used in transport, see here.'' Fagol Caspase recruitment domain-containing protein 16 is an enzyme that in humans is encoded by the ''CARD16'' gene In biology, the word gene (from , ; "...Wilhelm Johannse ...

. A different mechanism may function in ''Drosophila''. The true ground state of the flavin cofactor in ''Drosophila'' CRY is still debated, with some models indicating that the FAD is in an oxidized form, while others support a model in which the flavin cofactor exists in

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

radical form, •. Recently, researchers have observed that oxidized FAD is readily reduced to • by light. Furthermore, mutations that blocked photoreduction had no effect on light-induced degradation of CRY, while mutations that altered the stability of • destroyed CRY photoreceptor function. These observations provide support for a ground state of •. Researchers have also recently proposed a model in which is excited to its

doublet Doublet is a word derived from the Latin ''duplus'', "twofold, twice as much",