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Protein

Cryptochrome-2

Gene

Cry2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and NAMPT.By similarity

Cofactori

Protein has several cofactor binding sites:
  • FADBy similarityNote: Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket.By similarity
  • 5,10-methylenetetrahydrofolateBy similarityNote: Binds 1 5,10-methenyltetrahydrofolate non-covalently per subunit.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei270 – 2701FAD; via amide nitrogenBy similarity
Binding sitei307 – 3071FADBy similarity
Binding sitei373 – 3731FADBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi405 – 4073FADBy similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Photoreceptor protein, Receptor, Repressor

Keywords - Biological processi

Biological rhythms, Sensory transduction, Transcription, Transcription regulation

Keywords - Ligandi

Chromophore, FAD, Flavoprotein, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Cryptochrome-2
Gene namesi
Name:Cry2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620935. Cry2.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: Translocated to the nucleus through interaction with other Clock proteins such as PER2 or ARNTL.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 594594Cryptochrome-2PRO_0000261150Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei89 – 891PhosphoserineBy similarity
Cross-linki125 – 125Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki241 – 241Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei265 – 2651Phosphoserine; by MAPKBy similarity
Modified residuei298 – 2981PhosphoserineBy similarity
Cross-linki347 – 347Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki474 – 474Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki503 – 503Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei553 – 5531Phosphoserine; by GSK3-betaBy similarity
Modified residuei557 – 5571Phosphoserine; by DYRK1A and MAPKBy similarity

Post-translational modificationi

Phosphorylation on Ser-265 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity. Phosphorylation by CSKNe requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-553 and Ser-557 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-557 by DYRK1A promotes subsequent phosphorylation at Ser-553 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation.By similarity
Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-553 and Ser-557. Ubiquitination may be inhibited by PER2.By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ923I8.
PRIDEiQ923I8.

Expressioni

Tissue specificityi

Expressed in all tissues examined including heart, cerebellum, cerebral cortex, lung, liver, muscle, kidney and ovary. Highest levels in heart, liver and ovary. Highly expressed in the suprachiasmatic nucleus (SCN).1 Publication

Interactioni

Subunit structurei

Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with PER1 and PER2 C-terminal domains. Interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with NFIL3. Interacts with FBXL3 and FBXL21. FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites. FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD. Interacts with PPP5C (via TPR repeats); the interaction downregulates the PPP5C phosphatase activity on CSNK1E. AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction, at least, with NR3C1/GR is ligand dependent. Interacts with PRKDC and CIART.1 Publication

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-61214N.
STRINGi10116.ENSRNOP00000010142.

Structurei

3D structure databases

ProteinModelPortaliQ923I8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini21 – 150130Photolyase/cryptochrome alpha/betaAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni389 – 488100Required for inhibition of CLOCK-ARNTL-mediated transcriptionBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi2 – 54Poly-Ala

Sequence similaritiesi

Belongs to the DNA photolyase class-1 family.Curated

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ923I8.
PhylomeDBiQ923I8.

Family and domain databases

Gene3Di3.40.50.620. 1 hit.
InterProiIPR005101. Cryptochr/Photolyase_FAD-bd.
IPR006050. DNA_photolyase_N.
IPR014729. Rossmann-like_a/b/a_fold.
[Graphical view]
PfamiPF00875. DNA_photolyase. 1 hit.
PF03441. FAD_binding_7. 1 hit.
[Graphical view]
SUPFAMiSSF48173. SSF48173. 1 hit.
SSF52425. SSF52425. 1 hit.
PROSITEiPS51645. PHR_CRY_ALPHA_BETA. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q923I8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAAAAVVAAT VPVQSMGADG ASSVHWFRKG LRLHDNPALL AAVRGARCVR
60 70 80 90 100
CVYILDPWFA ASSSVGINRW RFLLQSLEDL DTSLRKLNSR LFVVRGQPAD
110 120 130 140 150
VFPRLFKEWG VTRLTFEYDS EPFGKERDAA IMKMAKEAGV EVVTENSHTL
160 170 180 190 200
YDLDRIIELN GQKPPLTYKR FQALISRMEL PKKPVGAVSS QHMENCRAEI
210 220 230 240 250
QENHDDTYGV PSLEELGFPT EGLGPAVWQG GETEALVRLD KHLERKAWVA
260 270 280 290 300
NYERPRMNAN SLLASPTGLS PYLRFGCLSC RLFYYRLWDL YRKVKRNSTP
310 320 330 340 350
PLSLFGQLLW REFFYTAATN NPRFDRMEGN PICIQIPWDR NPEALAKWAE
360 370 380 390 400
GKTGFPWIDA IMTQLRQEGW IHHLARHAVA CFLTRGDLWV SWESGVRVFD
410 420 430 440 450
ELLLDADFSV NAGSWMWLSC SAFFQQFFHC YCPVGFGRRT DPSGDYIRRY
460 470 480 490 500
LPKLKGFPSR YIYEPWNAPE SVQKAANCII GVDYPRPIVN HAETSRLNIE
510 520 530 540 550
RMKQIYQQLS RYRGLCLWAS VPSCVEDLSH PVAEPGSSQA GSISNTGPRP
560 570 580 590
LSSGPASPKR KLEAAEEPPG EELSKRARVT VTQMPAQEPP SKDS
Length:594
Mass (Da):67,223
Last modified:December 1, 2001 - v1
Checksum:i9B99F650E3845E11
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY033877 mRNA. Translation: AAK61419.1.
UniGeneiRn.21150.

Genome annotation databases

UCSCiRGD:620935. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY033877 mRNA. Translation: AAK61419.1.
UniGeneiRn.21150.

3D structure databases

ProteinModelPortaliQ923I8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61214N.
STRINGi10116.ENSRNOP00000010142.

Proteomic databases

PaxDbiQ923I8.
PRIDEiQ923I8.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

UCSCiRGD:620935. rat.

Organism-specific databases

RGDi620935. Cry2.

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ923I8.
PhylomeDBiQ923I8.

Miscellaneous databases

NextBioi621399.
PROiQ923I8.

Family and domain databases

Gene3Di3.40.50.620. 1 hit.
InterProiIPR005101. Cryptochr/Photolyase_FAD-bd.
IPR006050. DNA_photolyase_N.
IPR014729. Rossmann-like_a/b/a_fold.
[Graphical view]
PfamiPF00875. DNA_photolyase. 1 hit.
PF03441. FAD_binding_7. 1 hit.
[Graphical view]
SUPFAMiSSF48173. SSF48173. 1 hit.
SSF52425. SSF52425. 1 hit.
PROSITEiPS51645. PHR_CRY_ALPHA_BETA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Cloning and expression of cryptochrome2 cDNA in the rat."
    Eun B.-K., Lee B.J., Kang H.M.
    Mol. Cells 12:286-291(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
    Strain: Sprague-Dawley.
    Tissue: Brain.
  2. "Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5."
    Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.
    Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH PPP5C.

Entry informationi

Entry nameiCRY2_RAT
AccessioniPrimary (citable) accession number: Q923I8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: December 1, 2001
Last modified: November 11, 2015
This is version 88 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.