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Q16526 (CRY1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 109. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cryptochrome-1
Gene names
Name:CRY1
Synonyms:PHLL1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length586 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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, NR1D2, RORA, RORB and RORG, 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:BMAL1 independently of PER proteins and is found at CLOCK:BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK:BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. 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. Ref.5 Ref.6 Ref.11

Cofactor

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.

Binds 1 5,10-methenyltetrahydrofolate non-covalently per subunit.

Subunit structure

Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL or ARNTL2, 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 PPP5C (via TPR repeats). Interacts with of the 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. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Subcellular location

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

Induction

Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with ARNTL-CLOCK inhibition as part of the autoregulatory feedback loop.

Post-translational modification

Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL-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-568 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.

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 inhibit by PER2. Ref.8

Sequence similarities

Belongs to the DNA photolyase class-1 family.

Contains 1 photolyase/cryptochrome alpha/beta domain.

Ontologies

Keywords
   Biological processBiological rhythms
Sensory transduction
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandChromophore
FAD
Flavoprotein
Nucleotide-binding
   Molecular functionPhotoreceptor protein
Receptor
Repressor
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage induced protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

DNA repair

Inferred from electronic annotation. Source: InterPro

blue light signaling pathway

Non-traceable author statement Ref.1. Source: UniProtKB

circadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

gluconeogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

glucose homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of G-protein coupled receptor protein signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of glucocorticoid receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 12397359Ref.6PubMed 15147242. Source: BHF-UCL

negative regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

protein-chromophore linkage

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of DNA damage checkpoint

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

response to glucagon

Inferred from sequence or structural similarity. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from direct assay. Source: HPA

mitochondrion

Inferred from electronic annotation. Source: Ensembl

nucleolus

Inferred from direct assay. Source: HPA

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionDNA binding

Traceable author statement PubMed 9801304. Source: ProtInc

DNA photolyase activity

Inferred from electronic annotation. Source: InterPro

blue light photoreceptor activity

Non-traceable author statement Ref.1. Source: UniProtKB

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

double-stranded DNA binding

Inferred from direct assay PubMed 9801304. Source: UniProtKB

nuclear hormone receptor binding

Inferred from physical interaction Ref.11. Source: UniProtKB

nucleotide binding

Inferred from electronic annotation. Source: UniProtKB-KW

phosphatase binding

Inferred from physical interaction PubMed 9383998. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.8Ref.9Ref.10PubMed 21680841PubMed 9383998. Source: UniProtKB

transcription factor binding transcription factor activity

Inferred from direct assay PubMed 15147242. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 586586Cryptochrome-1
PRO_0000261140

Regions

Domain3 – 132130Photolyase/cryptochrome alpha/beta
Nucleotide binding387 – 3893FAD By similarity
Region371 – 470100Required for inhibition of CLOCK-ARNTL-mediated transcription By similarity

Sites

Binding site2521FAD; via amide nitrogen By similarity
Binding site2891FAD By similarity
Binding site3551FAD By similarity

Amino acid modifications

Modified residue711Phosphoserine; by AMPK By similarity
Modified residue2471Phosphoserine; by MAPK By similarity
Modified residue2801Phosphoserine; by AMPK By similarity
Modified residue5681Phosphoserine By similarity
Cross-link11Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link107Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link329Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link485Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Sequences

Sequence LengthMass (Da)Tools
Q16526 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 96A5B09A6364D3B9

FASTA58666,395
        10         20         30         40         50         60 
MGVNAVHWFR KGLRLHDNPA LKECIQGADT IRCVYILDPW FAGSSNVGIN RWRFLLQCLE 

        70         80         90        100        110        120 
DLDANLRKLN SRLFVIRGQP ADVFPRLFKE WNITKLSIEY DSEPFGKERD AAIKKLATEA 

       130        140        150        160        170        180 
GVEVIVRISH TLYDLDKIIE LNGGQPPLTY KRFQTLISKM EPLEIPVETI TSEVIEKCTT 

       190        200        210        220        230        240 
PLSDDHDEKY GVPSLEELGF DTDGLSSAVW PGGETEALTR LERHLERKAW VANFERPRMN 

       250        260        270        280        290        300 
ANSLLASPTG LSPYLRFGCL SCRLFYFKLT DLYKKVKKNS SPPLSLYGQL LWREFFYTAA 

       310        320        330        340        350        360 
TNNPRFDKME GNPICVQIPW DKNPEALAKW AEGRTGFPWI DAIMTQLRQE GWIHHLARHA 

       370        380        390        400        410        420 
VACFLTRGDL WISWEEGMKV FEELLLDADW SINAGSWMWL SCSSFFQQFF HCYCPVGFGR 

       430        440        450        460        470        480 
RTDPNGDYIR RYLPVLRGFP AKYIYDPWNA PEGIQKVAKC LIGVNYPKPM VNHAEASRLN 

       490        500        510        520        530        540 
IERMKQIYQQ LSRYRGLGLL ASVPSNPNGN GGFMGYSAEN IPGCSSSGSC SQGSGILHYA 

       550        560        570        580 
HGDSQQTHLL KQGRSSMGTG LSGGKRPSQE EDTQSIGPKV QRQSTN 

« Hide

References

« Hide 'large scale' references
[1]"Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins."
Hsu D.S., Zhao X., Zhao S., Kazantsev A., Wang R.-P., Todo T., Wei Y.-F., Sancar A.
Biochemistry 35:13871-13877(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
Tissue: Fibroblast.
[2]"Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors."
van der Spek P.J., Kobayashi K., Bootsma D., Takao M., Eker A.P.M., Yasui A.
Genomics 37:177-182(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
Tissue: Testis.
[3]"Similarity among the Drosophila (6-4)photolyase, a human photolyase homolog, and the DNA photolyase-blue-light photoreceptor family."
Todo T., Ryo H., Yamamoto K., Toh H., Inui T., Ayaki H., Nomura T., Ikenaga M.
Science 272:109-112(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
Tissue: Brain.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[5]"Light-independent role of CRY1 and CRY2 in the mammalian circadian clock."
Griffin E.A. Jr., Staknis D., Weitz C.J.
Science 286:768-771(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation."
Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R., Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I., Kato Y.
Biochem. Biophys. Res. Commun. 313:117-124(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"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.
[8]"SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins."
Busino L., Bassermann F., Maiolica A., Lee C., Nolan P.M., Godinho S.I., Draetta G.F., Pagano M.
Science 316:900-904(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, UBIQUITINATION BY FBXL3, INTERACTION WITH FBXL3.
[9]"Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis."
Zhang E.E., Liu Y., Dentin R., Pongsawakul P.Y., Liu A.C., Hirota T., Nusinow D.A., Sun X., Landais S., Kodama Y., Brenner D.A., Montminy M., Kay S.A.
Nat. Med. 16:1152-1156(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GNAS.
[10]"Biochemical analysis of the canonical model for the mammalian circadian clock."
Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.
J. Biol. Chem. 286:25891-25902(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PER2.
[11]"Cryptochromes mediate rhythmic repression of the glucocorticoid receptor."
Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W., Downes M., Evans R.M.
Nature 480:552-556(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS NR3C1 REPRESSOR, INTERACTION WITH AR; NR1D1; NR3C1; RORA AND RORC.
[12]"Metabolism and the circadian clock converge."
Eckel-Mahan K., Sassone-Corsi P.
Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[13]"Molecular architecture of the mammalian circadian clock."
Partch C.L., Green C.B., Takahashi J.S.
Trends Cell Biol. 24:90-99(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
+Additional computationally mapped references.

Web resources

Wikipedia

Cryptochrome entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D84657 mRNA. Translation: BAA12710.1.
D83702 mRNA. Translation: BAA12068.1.
BC030519 mRNA. Translation: AAH30519.1.
CCDSCCDS9112.1.
RefSeqNP_004066.1. NM_004075.4.
UniGeneHs.151573.

3D structure databases

ProteinModelPortalQ16526.
SMRQ16526. Positions 3-489.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107797. 25 interactions.
IntActQ16526. 12 interactions.
MINTMINT-1437226.
STRING9606.ENSP00000008527.

PTM databases

PhosphoSiteQ16526.

Polymorphism databases

DMDM74735764.

Proteomic databases

MaxQBQ16526.
PaxDbQ16526.
PRIDEQ16526.

Protocols and materials databases

DNASU1407.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000008527; ENSP00000008527; ENSG00000008405.
GeneID1407.
KEGGhsa:1407.
UCSCuc001tmi.4. human.

Organism-specific databases

CTD1407.
GeneCardsGC12M107385.
HGNCHGNC:2384. CRY1.
HPACAB018762.
HPA047596.
MIM601933. gene.
neXtProtNX_Q16526.
PharmGKBPA26904.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0415.
HOGENOMHOG000245622.
HOVERGENHBG053470.
InParanoidQ16526.
KOK02295.
OMAFDTDGLP.
OrthoDBEOG7QG43M.
PhylomeDBQ16526.
TreeFamTF323191.

Enzyme and pathway databases

ReactomeREACT_24941. Circadian Clock.

Gene expression databases

ArrayExpressQ16526.
BgeeQ16526.
CleanExHS_CRY1.
GenevestigatorQ16526.

Family and domain databases

Gene3D3.40.50.620. 1 hit.
InterProIPR006050. DNA_photolyase_N.
IPR005101. Photolyase_FAD-bd/Cryptochr_C.
IPR014729. Rossmann-like_a/b/a_fold.
[Graphical view]
PfamPF00875. DNA_photolyase. 1 hit.
PF03441. FAD_binding_7. 1 hit.
[Graphical view]
SUPFAMSSF48173. SSF48173. 1 hit.
SSF52425. SSF52425. 1 hit.
PROSITEPS51645. PHR_CRY_ALPHA_BETA. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCRY1. human.
GenomeRNAi1407.
NextBio5753.
PROQ16526.
SOURCESearch...

Entry information

Entry nameCRY1_HUMAN
AccessionPrimary (citable) accession number: Q16526
Entry history
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 109 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM