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Protein

Cryptochrome-1

Gene

Cry1

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. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1, ATF4, MTA1, KLF10 and NAMPT. May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). 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.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 sitei252 – 2521FAD; via amide nitrogenBy similarity
Binding sitei289 – 2891FADBy similarity
Binding sitei355 – 3551FADBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi387 – 3893FADBy 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-1
Gene namesi
Name:Cry1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 7

Organism-specific databases

RGDi735083. Cry1.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: Translocated to the nucleus through interaction with other clock proteins such as PER2 or ARNTL/BMAL1.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 588588Cryptochrome-1PRO_0000261143Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei71 – 711Phosphoserine; by AMPKBy similarity
Cross-linki107 – 107Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki159 – 159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei247 – 2471Phosphoserine; by MAPKBy similarity
Modified residuei280 – 2801Phosphoserine; by AMPKBy similarity
Cross-linki329 – 329Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki456 – 456Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki485 – 485Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei570 – 5701PhosphoserineBy similarity

Post-translational modificationi

Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-570 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC (By similarity).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 CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2.By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ32Q86.
PRIDEiQ32Q86.

PTM databases

iPTMnetiQ32Q86.
PhosphoSiteiQ32Q86.

Expressioni

Inductioni

Expression is regulated by light and circadian rhythms. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12).1 Publication

Gene expression databases

BgeeiENSRNOG00000006622.
GenevisibleiQ32Q86. RN.

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 TIMELESS. Interacts directly with PER1 and PER2 C-terminal domains. Interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with FBXL21. Interacts with FBXL3. Interacts with CLOCK-ARNTL/BMAL1 independently of PER2 and DNA. Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent. Interacts with PRKDC. Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations. Interacts with PRMT5. Interacts with EZH2 (By similarity). Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity). Interacts with PPP5C (via TPR repeats).By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-61213N.
STRINGi10116.ENSRNOP00000009124.

Structurei

3D structure databases

ProteinModelPortaliQ32Q86.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini3 – 132130Photolyase/cryptochrome alpha/betaAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni371 – 470100Required for inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptionBy similarityAdd
BLAST
Regioni471 – 49323Interaction with TIMELESSBy similarityAdd
BLAST

Sequence similaritiesi

Belongs to the DNA photolyase class-1 family.Curated

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
GeneTreeiENSGT00500000044813.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ32Q86.
KOiK02295.
OMAiYSQGSGI.
OrthoDBiEOG091G07M3.

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.

Q32Q86-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGVNAVHWFR KGLRLHDNPA LKECIQGADT IRCVYILDPW FAGSSNVGIN
60 70 80 90 100
RWRFLLQCLE DLDANLRKLN SRLFVIRGQP ADVFPRLFKE WNITKLSIEY
110 120 130 140 150
DSEPFGKERD AAIKKLATEA GVEVIVRISH TLYDLDKIIE LNGGQPPLTY
160 170 180 190 200
KRFQTLVSKM EPLEMPADTI TSDVIGKCTT PLSDDHDEKY GVPSLEELGF
210 220 230 240 250
DTDGLSSAVW PGGETEALTR LERHLERKAW VANFERPRMN ANSLLASPTG
260 270 280 290 300
LSPYLRFGCL SCRLFYFKLT DLYKKVKKNS SPPLSLYGQL LWREFFYTAA
310 320 330 340 350
TNNPRFDKME GNPICVQIPW DKNPEALAKW AEGRTGFPWI DAIMTQLRQE
360 370 380 390 400
GWIHHLARHA VACFLTRGDL WISWEEGMKV FEELLLDADW SINAGSWMWL
410 420 430 440 450
SCSSFFQQFF HCYCPVGFGR RTDPNGDYIR RYLPVLRGFP AKYIYDPWNA
460 470 480 490 500
PEGIQKVAKC LIGVNYPKPM VNHAEASRLN IERMKQIYQQ LSRYRGLGLL
510 520 530 540 550
ASVPSNPNGN GGLMGYAPGE NVPSGGSGGG NCSQGSGILH YAHGDSQQTN
560 570 580
PLKQGRSSMG TGLSSGKRPS QEEDAQSVGP KVQRQSSN
Length:588
Mass (Da):66,230
Last modified:December 6, 2005 - v1
Checksum:i5D61B98485AFC77E
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti33 – 331C → W in AAQ11980 (PubMed:15529004).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF545855 mRNA. Translation: AAQ11980.1.
BC107677 mRNA. Translation: AAI07678.1.
RefSeqiNP_942045.2. NM_198750.2.
XP_008763447.1. XM_008765225.1.
UniGeneiRn.43646.

Genome annotation databases

EnsembliENSRNOT00000009124; ENSRNOP00000009124; ENSRNOG00000006622.
GeneIDi299691.
KEGGirno:299691.
UCSCiRGD:735083. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF545855 mRNA. Translation: AAQ11980.1.
BC107677 mRNA. Translation: AAI07678.1.
RefSeqiNP_942045.2. NM_198750.2.
XP_008763447.1. XM_008765225.1.
UniGeneiRn.43646.

3D structure databases

ProteinModelPortaliQ32Q86.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61213N.
STRINGi10116.ENSRNOP00000009124.

PTM databases

iPTMnetiQ32Q86.
PhosphoSiteiQ32Q86.

Proteomic databases

PaxDbiQ32Q86.
PRIDEiQ32Q86.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000009124; ENSRNOP00000009124; ENSRNOG00000006622.
GeneIDi299691.
KEGGirno:299691.
UCSCiRGD:735083. rat.

Organism-specific databases

CTDi1407.
RGDi735083. Cry1.

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
GeneTreeiENSGT00500000044813.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ32Q86.
KOiK02295.
OMAiYSQGSGI.
OrthoDBiEOG091G07M3.

Miscellaneous databases

PROiQ32Q86.

Gene expression databases

BgeeiENSRNOG00000006622.
GenevisibleiQ32Q86. RN.

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...

Entry informationi

Entry nameiCRY1_RAT
AccessioniPrimary (citable) accession number: Q32Q86
Secondary accession number(s): Q717B5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: December 6, 2005
Last modified: September 7, 2016
This is version 87 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.