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Protein

Cryptochrome-2

Gene

CRY2

Organism
Homo sapiens (Human)
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. Represses the CLOCK-ARNTL/BMAL1 induced transcription of NAMPT (By similarity).By similarity3 Publications

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

Enzyme 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 sitei271FAD; via amide nitrogenBy similarity1
Binding sitei308FADBy similarity1
Binding sitei374FADBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi406 – 408FADBy similarity3

GO - Molecular functioni

  • blue light photoreceptor activity Source: UniProtKB
  • damaged DNA binding Source: UniProtKB
  • DNA binding Source: UniProtKB
  • FAD binding Source: UniProtKB
  • phosphatase binding Source: UniProtKB
  • single-stranded DNA binding Source: UniProtKB
  • transcription factor activity, transcription factor binding Source: BHF-UCL
  • transcription regulatory region sequence-specific DNA binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

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

Enzyme and pathway databases

ReactomeiR-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-400253. Circadian Clock.

Names & Taxonomyi

Protein namesi
Recommended name:
Cryptochrome-2
Gene namesi
Name:CRY2
Synonyms:KIAA0658
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:2385. CRY2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: HPA
  • extracellular region Source: MGI
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi1408.
OpenTargetsiENSG00000121671.
PharmGKBiPA26905.

Polymorphism and mutation databases

BioMutaiCRY2.
DMDMi118572252.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002611481 – 593Cryptochrome-2Add BLAST593

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki126Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki242Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei266Phosphoserine; by MAPKBy similarity1
Cross-linki348Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki475Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki504Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei554Phosphoserine; by GSK3-betaBy similarity1
Modified residuei558Phosphoserine; by DYRK1A and MAPKBy similarity1

Post-translational modificationi

Phosphorylation on Ser-266 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-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 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-554 and Ser-558. Ubiquitination may be inhibited by PER2.3 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ49AN0.
MaxQBiQ49AN0.
PaxDbiQ49AN0.
PeptideAtlasiQ49AN0.
PRIDEiQ49AN0.

PTM databases

iPTMnetiQ49AN0.
PhosphoSitePlusiQ49AN0.

Expressioni

Tissue specificityi

Expressed in all tissues examined including fetal brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Highest levels in heart and skeletal muscle.2 Publications

Gene expression databases

BgeeiENSG00000121671.
CleanExiHS_CRY2.
ExpressionAtlasiQ49AN0. baseline and differential.

Organism-specific databases

HPAiHPA037577.

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 (PubMed:17463251). Interacts with 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 (PubMed:16790549). AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction, at least, with NR3C1/GR is ligand dependent. Interacts with PRKDC and CIART. Interacts with ISCA1 (in vitro) (PubMed:26569474).3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CTBP1Q13363-23EBI-2212355,EBI-10171858
MTUS2Q5JR593EBI-2212355,EBI-742948
PDE9AO760833EBI-2212355,EBI-742764

GO - Molecular functioni

  • phosphatase binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi107798. 154 interactors.
DIPiDIP-47396N.
IntActiQ49AN0. 11 interactors.
STRINGi9606.ENSP00000406751.

Structurei

3D structure databases

DisProtiDP00473.
ProteinModelPortaliQ49AN0.
SMRiQ49AN0.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini22 – 151Photolyase/cryptochrome alpha/betaAdd BLAST130

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni390 – 489Required for inhibition of CLOCK-ARNTL-mediated transcriptionBy similarityAdd BLAST100

Sequence similaritiesi

Belongs to the DNA photolyase class-1 family.Curated

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
GeneTreeiENSGT00500000044813.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ49AN0.
KOiK02295.
PhylomeDBiQ49AN0.

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]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q49AN0-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAATVATAAA VAPAPAPGTD SASSVHWFRK GLRLHDNPAL LAAVRGARCV
60 70 80 90 100
RCVYILDPWF AASSSVGINR WRFLLQSLED LDTSLRKLNS RLFVVRGQPA
110 120 130 140 150
DVFPRLFKEW GVTRLTFEYD SEPFGKERDA AIMKMAKEAG VEVVTENSHT
160 170 180 190 200
LYDLDRIIEL NGQKPPLTYK RFQAIISRME LPKKPVGLVT SQQMESCRAE
210 220 230 240 250
IQENHDETYG VPSLEELGFP TEGLGPAVWQ GGETEALARL DKHLERKAWV
260 270 280 290 300
ANYERPRMNA NSLLASPTGL SPYLRFGCLS CRLFYYRLWD LYKKVKRNST
310 320 330 340 350
PPLSLFGQLL WREFFYTAAT NNPRFDRMEG NPICIQIPWD RNPEALAKWA
360 370 380 390 400
EGKTGFPWID AIMTQLRQEG WIHHLARHAV ACFLTRGDLW VSWESGVRVF
410 420 430 440 450
DELLLDADFS VNAGSWMWLS CSAFFQQFFH CYCPVGFGRR TDPSGDYIRR
460 470 480 490 500
YLPKLKAFPS RYIYEPWNAP ESIQKAAKCI IGVDYPRPIV NHAETSRLNI
510 520 530 540 550
ERMKQIYQQL SRYRGLCLLA SVPSCVEDLS HPVAEPSSSQ AGSMSSAGPR
560 570 580 590
PLPSGPASPK RKLEAAEEPP GEELSKRARV AELPTPELPS KDA
Length:593
Mass (Da):66,947
Last modified:November 28, 2006 - v2
Checksum:iBF380424092BEBFB
GO
Isoform 2 (identifier: Q49AN0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-72: MAATVATAAA...SSSVGINRWR → MPAPPGRTHTW

Note: No experimental confirmation available.Curated
Show »
Length:532
Mass (Da):60,593
Checksum:i07E1FCDFAC27731A
GO

Sequence cautioni

The sequence AAH35161 differs from that shown. Probable cloning artifact. Aberrant splice sites.Curated
The sequence BAG57993 differs from that shown. Reason: Erroneous termination at position 110. Translated as Trp.Curated
The sequence BAG57993 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS.Curated
The sequence BAG64048 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti422S → G in AAH35161 (PubMed:15489334).Curated1
Isoform 2 (identifier: Q49AN0-2)
Sequence conflicti9H → L in BAG57993 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0389701 – 72MAATV…INRWR → MPAPPGRTHTW in isoform 2. 1 PublicationAdd BLAST72

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK294904 mRNA. Translation: BAG57993.1. Sequence problems.
AK302865 mRNA. Translation: BAG64048.1. Different initiation.
AC068385 Genomic DNA. No translation available.
KF455380 Genomic DNA. No translation available.
BC035161 mRNA. Translation: AAH35161.1. Sequence problems.
BC041814 mRNA. Translation: AAH41814.1.
AB014558 mRNA. Translation: BAA31633.1.
CCDSiCCDS44576.1. [Q49AN0-2]
RefSeqiNP_001120929.1. NM_001127457.2. [Q49AN0-2]
NP_066940.2. NM_021117.3.
UniGeneiHs.532491.

Genome annotation databases

EnsembliENST00000417225; ENSP00000397419; ENSG00000121671. [Q49AN0-2]
ENST00000616080; ENSP00000484684; ENSG00000121671. [Q49AN0-1]
GeneIDi1408.
KEGGihsa:1408.
UCSCiuc009ykw.4. human. [Q49AN0-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

Wikipedia

Cryptochrome entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK294904 mRNA. Translation: BAG57993.1. Sequence problems.
AK302865 mRNA. Translation: BAG64048.1. Different initiation.
AC068385 Genomic DNA. No translation available.
KF455380 Genomic DNA. No translation available.
BC035161 mRNA. Translation: AAH35161.1. Sequence problems.
BC041814 mRNA. Translation: AAH41814.1.
AB014558 mRNA. Translation: BAA31633.1.
CCDSiCCDS44576.1. [Q49AN0-2]
RefSeqiNP_001120929.1. NM_001127457.2. [Q49AN0-2]
NP_066940.2. NM_021117.3.
UniGeneiHs.532491.

3D structure databases

DisProtiDP00473.
ProteinModelPortaliQ49AN0.
SMRiQ49AN0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107798. 154 interactors.
DIPiDIP-47396N.
IntActiQ49AN0. 11 interactors.
STRINGi9606.ENSP00000406751.

PTM databases

iPTMnetiQ49AN0.
PhosphoSitePlusiQ49AN0.

Polymorphism and mutation databases

BioMutaiCRY2.
DMDMi118572252.

Proteomic databases

EPDiQ49AN0.
MaxQBiQ49AN0.
PaxDbiQ49AN0.
PeptideAtlasiQ49AN0.
PRIDEiQ49AN0.

Protocols and materials databases

DNASUi1408.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000417225; ENSP00000397419; ENSG00000121671. [Q49AN0-2]
ENST00000616080; ENSP00000484684; ENSG00000121671. [Q49AN0-1]
GeneIDi1408.
KEGGihsa:1408.
UCSCiuc009ykw.4. human. [Q49AN0-1]

Organism-specific databases

CTDi1408.
DisGeNETi1408.
GeneCardsiCRY2.
H-InvDBHIX0201587.
HGNCiHGNC:2385. CRY2.
HPAiHPA037577.
MIMi603732. gene.
neXtProtiNX_Q49AN0.
OpenTargetsiENSG00000121671.
PharmGKBiPA26905.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.
GeneTreeiENSGT00500000044813.
HOGENOMiHOG000245622.
HOVERGENiHBG053470.
InParanoidiQ49AN0.
KOiK02295.
PhylomeDBiQ49AN0.

Enzyme and pathway databases

ReactomeiR-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-400253. Circadian Clock.

Miscellaneous databases

ChiTaRSiCRY2. human.
GenomeRNAii1408.
PROiQ49AN0.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000121671.
CleanExiHS_CRY2.
ExpressionAtlasiQ49AN0. baseline and differential.

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 nameiCRY2_HUMAN
AccessioniPrimary (citable) accession number: Q49AN0
Secondary accession number(s): B4DH32
, B4DZD6, O75148, Q8IV71
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: November 28, 2006
Last modified: November 2, 2016
This is version 112 of the entry and version 2 of the sequence. [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. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. 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.