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Protein

Cryptochrome-1

Gene

CRY1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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. Represses the CLOCK-ARNTL/BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). 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 similarity5 Publications

Cofactori

Protein has several cofactor binding sites:
  • FADNote: 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.
  • (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateNote: Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.

Activity regulationi

KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei252FAD; via amide nitrogenBy similarity1
Binding sitei289FADBy similarity1
Binding sitei355FADBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi387 – 389FADBy similarity3

GO - Molecular functioni

  • blue light photoreceptor activity Source: UniProtKB
  • DNA binding Source: ProtInc
  • double-stranded DNA binding Source: UniProtKB
  • E-box binding Source: Ensembl
  • histone deacetylase binding Source: Ensembl
  • nuclear hormone receptor binding Source: UniProtKB
  • nucleotide binding Source: UniProtKB-KW
  • phosphatase binding Source: UniProtKB
  • protein kinase binding Source: Ensembl

GO - Biological processi

Keywordsi

Molecular functionPhotoreceptor protein, Receptor, Repressor
Biological processBiological rhythms, Sensory transduction, Transcription, Transcription regulation
LigandChromophore, FAD, Flavoprotein, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-400253 Circadian Clock
SIGNORiQ16526

Names & Taxonomyi

Protein namesi
Recommended name:
Cryptochrome-1
Gene namesi
Name:CRY1
Synonyms:PHLL1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000008405.11
HGNCiHGNC:2384 CRY1
MIMi601933 gene
neXtProtiNX_Q16526

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Delayed sleep phase syndrome (DSPS)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry. An adenine-to-cytosine transversion within the 5'splice site following exon 11 has been found in multiple members of a DSPD family and segregates with the disorder with autosomal dominant inheritance pattern. This variant is predicted to cause exon 11 skipping and in-frame deletion of 24 residues in the C-terminal region of CRY1. Functional studies show that the mutated protein acts as a more potent transcriptional repressor than wild-type, causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms.1 Publication
Disease descriptionA circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPS have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities.
See also OMIM:614163

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi387D → N: Loss of binding to KL001. 1 Publication1
Mutagenesisi393N → D: Loss of binding to KL001. 1 Publication1

Organism-specific databases

DisGeNETi1407
MIMi614163 phenotype
OpenTargetsiENSG00000008405
PharmGKBiPA26904

Chemistry databases

GuidetoPHARMACOLOGYi2876

Polymorphism and mutation databases

DMDMi74735764

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002611401 – 586Cryptochrome-1Add BLAST586

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki11Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei71Phosphoserine; by AMPKBy similarity1
Cross-linki107Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei247Phosphoserine; by MAPKBy similarity1
Modified residuei280Phosphoserine; by AMPKBy similarity1
Cross-linki329Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki485Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei568PhosphoserineBy similarity1

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-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 inhibited by PER2.3 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ16526
MaxQBiQ16526
PaxDbiQ16526
PeptideAtlasiQ16526
PRIDEiQ16526
ProteomicsDBi60893

PTM databases

iPTMnetiQ16526
PhosphoSitePlusiQ16526

Expressioni

Inductioni

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/BMAL1-CLOCK inhibition as part of the autoregulatory feedback loop.

Gene expression databases

BgeeiENSG00000008405 Expressed in 233 organ(s), highest expression level in oocyte
CleanExiHS_CRY1
ExpressionAtlasiQ16526 baseline and differential
GenevisibleiQ16526 HS

Organism-specific databases

HPAiCAB018762

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 PPP5C (via TPR repeats). 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).By similarity7 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi107797, 147 interactors
ComplexPortaliCPX-3219 Cry1-Per2 complex
CPX-3222 Cry1-Per1 complex
CPX-3223 Cry1-Per3 complex
CORUMiQ16526
DIPiDIP-56602N
IntActiQ16526, 24 interactors
STRINGi9606.ENSP00000008527

Structurei

3D structure databases

ProteinModelPortaliQ16526
SMRiQ16526
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini3 – 132Photolyase/cryptochrome alpha/betaAdd BLAST130

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni371 – 470Required for inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptionBy similarityAdd BLAST100
Regioni471 – 493Interaction with TIMELESSBy similarityAdd BLAST23

Sequence similaritiesi

Belongs to the DNA photolyase class-1 family.Curated

Phylogenomic databases

eggNOGiKOG0133 Eukaryota
COG0415 LUCA
GeneTreeiENSGT00500000044813
HOGENOMiHOG000245622
HOVERGENiHBG053470
InParanoidiQ16526
KOiK02295
OMAiIHNRPRQ
OrthoDBiEOG091G07M3
PhylomeDBiQ16526
TreeFamiTF323191

Family and domain databases

Gene3Di3.40.50.620, 1 hit
InterProiView protein in InterPro
IPR036134 Crypto/Photolyase_FAD-like_sf
IPR036155 Crypto/Photolyase_N_sf
IPR005101 Cryptochr/Photolyase_FAD-bd
IPR006050 DNA_photolyase_N
IPR014729 Rossmann-like_a/b/a_fold
PfamiView protein in Pfam
PF00875 DNA_photolyase, 1 hit
PF03441 FAD_binding_7, 1 hit
SUPFAMiSSF48173 SSF48173, 1 hit
SSF52425 SSF52425, 1 hit
PROSITEiView protein in PROSITE
PS51645 PHR_CRY_ALPHA_BETA, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

Q16526-1 [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
KRFQTLISKM EPLEIPVETI TSEVIEKCTT 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 GGFMGYSAEN IPGCSSSGSC SQGSGILHYA HGDSQQTHLL
560 570 580
KQGRSSMGTG LSGGKRPSQE EDTQSIGPKV QRQSTN
Length:586
Mass (Da):66,395
Last modified:November 1, 1996 - v1
Checksum:i96A5B09A6364D3B9
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0YHT0H0YHT0_HUMAN
Cryptochrome-1
CRY1
106Annotation score:

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D84657 mRNA Translation: BAA12710.1
D83702 mRNA Translation: BAA12068.1
BC030519 mRNA Translation: AAH30519.1
CCDSiCCDS9112.1
RefSeqiNP_004066.1, NM_004075.4
UniGeneiHs.151573

Genome annotation databases

EnsembliENST00000008527; ENSP00000008527; ENSG00000008405
GeneIDi1407
KEGGihsa:1407
UCSCiuc001tmi.5 human

Similar proteinsi

Cross-referencesi

Web resourcesi

Wikipedia

Cryptochrome entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D84657 mRNA Translation: BAA12710.1
D83702 mRNA Translation: BAA12068.1
BC030519 mRNA Translation: AAH30519.1
CCDSiCCDS9112.1
RefSeqiNP_004066.1, NM_004075.4
UniGeneiHs.151573

3D structure databases

ProteinModelPortaliQ16526
SMRiQ16526
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107797, 147 interactors
ComplexPortaliCPX-3219 Cry1-Per2 complex
CPX-3222 Cry1-Per1 complex
CPX-3223 Cry1-Per3 complex
CORUMiQ16526
DIPiDIP-56602N
IntActiQ16526, 24 interactors
STRINGi9606.ENSP00000008527

Chemistry databases

GuidetoPHARMACOLOGYi2876

PTM databases

iPTMnetiQ16526
PhosphoSitePlusiQ16526

Polymorphism and mutation databases

DMDMi74735764

Proteomic databases

EPDiQ16526
MaxQBiQ16526
PaxDbiQ16526
PeptideAtlasiQ16526
PRIDEiQ16526
ProteomicsDBi60893

Protocols and materials databases

DNASUi1407
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000008527; ENSP00000008527; ENSG00000008405
GeneIDi1407
KEGGihsa:1407
UCSCiuc001tmi.5 human

Organism-specific databases

CTDi1407
DisGeNETi1407
EuPathDBiHostDB:ENSG00000008405.11
GeneCardsiCRY1
HGNCiHGNC:2384 CRY1
HPAiCAB018762
MIMi601933 gene
614163 phenotype
neXtProtiNX_Q16526
OpenTargetsiENSG00000008405
PharmGKBiPA26904
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0133 Eukaryota
COG0415 LUCA
GeneTreeiENSGT00500000044813
HOGENOMiHOG000245622
HOVERGENiHBG053470
InParanoidiQ16526
KOiK02295
OMAiIHNRPRQ
OrthoDBiEOG091G07M3
PhylomeDBiQ16526
TreeFamiTF323191

Enzyme and pathway databases

ReactomeiR-HSA-400253 Circadian Clock
SIGNORiQ16526

Miscellaneous databases

ChiTaRSiCRY1 human
GenomeRNAii1407
PROiPR:Q16526
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000008405 Expressed in 233 organ(s), highest expression level in oocyte
CleanExiHS_CRY1
ExpressionAtlasiQ16526 baseline and differential
GenevisibleiQ16526 HS

Family and domain databases

Gene3Di3.40.50.620, 1 hit
InterProiView protein in InterPro
IPR036134 Crypto/Photolyase_FAD-like_sf
IPR036155 Crypto/Photolyase_N_sf
IPR005101 Cryptochr/Photolyase_FAD-bd
IPR006050 DNA_photolyase_N
IPR014729 Rossmann-like_a/b/a_fold
PfamiView protein in Pfam
PF00875 DNA_photolyase, 1 hit
PF03441 FAD_binding_7, 1 hit
SUPFAMiSSF48173 SSF48173, 1 hit
SSF52425 SSF52425, 1 hit
PROSITEiView protein in PROSITE
PS51645 PHR_CRY_ALPHA_BETA, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCRY1_HUMAN
AccessioniPrimary (citable) accession number: Q16526
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: November 1, 1996
Last modified: November 7, 2018
This is version 149 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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