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Mus musculus (Mouse)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


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 atCLOCK-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 ACSL4.22 Publications


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
  • (6R)-5,10-methylenetetrahydrofolateBy similarityNote: Binds 1 5,10-methenyltetrahydrofolate (MTHF) 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. KL001-mediated CRY1 stabilization can inhibit glucagon-induced gluconeogenesis in primary hepatocytes.1 Publication


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


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

GO - Molecular functioni

  • core promoter binding Source: UniProtKB
  • core promoter sequence-specific DNA binding Source: UniProtKB
  • double-stranded DNA binding Source: UniProtKB
  • histone deacetylase binding Source: UniProtKB
  • kinase binding Source: UniProtKB
  • nuclear hormone receptor binding Source: UniProtKB
  • nucleotide binding Source: UniProtKB-KW
  • phosphatase binding Source: MGI
  • photoreceptor activity Source: UniProtKB-KW
  • protein kinase binding Source: UniProtKB
  • transcription factor activity, transcription factor binding Source: MGI
  • transcription factor binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

GO - Biological processi

  • circadian regulation of gene expression Source: UniProtKB
  • circadian rhythm Source: MGI
  • DNA damage induced protein phosphorylation Source: UniProtKB
  • entrainment of circadian clock by photoperiod Source: UniProtKB
  • gluconeogenesis Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • lipid storage Source: UniProtKB
  • negative regulation of circadian rhythm Source: UniProtKB
  • negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
  • negative regulation of glucocorticoid secretion Source: UniProtKB
  • negative regulation of G-protein coupled receptor protein signaling pathway Source: UniProtKB
  • negative regulation of protein ubiquitination Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • protein-chromophore linkage Source: UniProtKB-KW
  • regulation of circadian rhythm Source: UniProtKB
  • regulation of DNA damage checkpoint Source: UniProtKB
  • response to glucagon Source: UniProtKB
  • response to insulin Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW


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

Enzyme and pathway databases

ReactomeiR-MMU-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-MMU-1368110. Bmal1:Clock,Npas2 activates circadian gene expression.
R-MMU-400253. Circadian Clock.
R-MMU-508751. Circadian Clock.

Names & Taxonomyi

Protein namesi
Recommended name:
Gene namesi
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1270841. Cry1.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: Reactome
  • mitochondrion Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice show an advanced phase shift (around 4 hours) in the expression of DBP, NR1D1 and PER1 genes in the liver. Double knockouts of CRY1 and CRY2 show slightly decrease body weight and lose the cycling rhythmicity of feeding behavior, energy expenditure and glucocorticoids expression. Glucose homeostasis is severely disrupted and animals exhibit elevated blood glucose in response to acute feeding after an overnight fast as well as severely impaired glucose clearance in a glucose tolerance test. When challenged with high-fat diet, animals rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. They exhibit hyperinsulinemia and selective insulin resistance in the liver and muscle but show high insulin sensitivity in adipose tissue and consequent increased lipid uptake. Mice display enlarged gonadal, subcutaneous and perirenal fat deposits with adipocyte hypertrophy and increased lipied accumulation in liver.5 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi71S → A: Phosphomimetic mutant that leads to stabilization of the protein; when associated with A-280. 1 Publication1
Mutagenesisi71S → D: Phosphomimetic mutant that leads to destabilization of the protein and abolishes ability to bind PER2; when associated with D-280. 1 Publication1
Mutagenesisi107K → R: Sensitive to FBXL3-ediated degradation but noz affected by expression of FBXL21. 1 Publication1
Mutagenesisi224H → E: Reduces affinity for FBXL3. 1 Publication1
Mutagenesisi247S → A: Reduced MAPK-catalyzed in vitro phosphorylation. No effect on inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. 2 Publications1
Mutagenesisi247S → D: Reduced inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. 2 Publications1
Mutagenesisi280S → A: Phosphomimetic mutant that leads to stabilization of the protein; when associated with A-71. 1 Publication1
Mutagenesisi280S → D: Phosphomimetic mutant that leads to destabilization of the protein and abolishes ability to bind PER2; when associated with D-71. 1 Publication1
Mutagenesisi336G → D: Abolishes transcriptional repression of target genes. Abolishes interaction with PER2. 1
Mutagenesisi382 – 383EE → RR: Decreases transcriptional repression of target genes. Decreases FBXL3 binding. Increases PER2 binding. 1 Publication2
Mutagenesisi405F → A: Decreases affinity for FBXL3. Slightly increases affinity for PER2. 1 Publication1
Mutagenesisi485K → D or E: Strongly reduces FBXL3 binding. Reduces PER2 binding. 1 Publication1
Mutagenesisi551S → A: No effect on circadian period length and protein stability. 1 Publication1
Mutagenesisi551S → D: No effect on circadian period length and protein stability. 1 Publication1
Mutagenesisi564S → A: No effect on circadian period length and protein stability. 1 Publication1
Mutagenesisi564S → D: No effect on circadian period length and protein stability. 1 Publication1
Mutagenesisi588S → A: No effect on circadian period length and protein stability. 1 Publication1
Mutagenesisi588S → D: Lengthen circadian period. No effect on repressive activity. Increases protein stability. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002611421 – 606Cryptochrome-1Add BLAST606

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki11Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei71Phosphoserine; by AMPK1 Publication1
Cross-linki107Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei247Phosphoserine; by MAPK1 Publication1
Modified residuei280Phosphoserine; by AMPK1 Publication1
Cross-linki329Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki485Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei588Phosphoserine1 Publication1

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-588 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.4 Publications
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 PER2.5 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases


PTM databases



Tissue specificityi

Expressed in all tissues examined including heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Higher levels in brain, liver and testis. In the retina, highly expressed in the ganglion cell layer (GCL) and in the inner nuclear layer (INL). Evenly distributed in central and peripheral retina. In the brain, highly expressed in the suprachiasmatic nucleus (SCN). High levels in cerebral cortical layers particularly in the pyramidial cell layer of the hippocampus, the granular cell layer of the dentate gyrus (DG) and the pyramidal cell layer of the piriform cortex (PFC).5 Publications


Oscillates diurnally, rhythmic expression in the early night is critical for clock function (at ptrotein level). In SCN, exhibits circadian rhythm expression with highest levels during the light phase at CT10. No detectable expression after 8 hours in the dark. Circadian oscillations also observed in liver, skeletal muscle and cerebellum, but not in testis.8 Publications

Gene expression databases

GenevisibleiP97784. MM.


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 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. Interacts with PRMT5. Interacts with EZH2. Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3.21 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • histone deacetylase binding Source: UniProtKB
  • kinase binding Source: UniProtKB
  • nuclear hormone receptor binding Source: UniProtKB
  • phosphatase binding Source: MGI
  • protein kinase binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi198906. 29 interactors.
IntActiP97784. 29 interactors.


Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi4 – 11Combined sources8
Beta strandi14 – 17Combined sources4
Helixi19 – 25Combined sources7
Beta strandi29 – 37Combined sources9
Turni39 – 44Combined sources6
Helixi49 – 67Combined sources19
Turni68 – 70Combined sources3
Beta strandi73 – 78Combined sources6
Helixi80 – 91Combined sources12
Beta strandi93 – 99Combined sources7
Helixi104 – 119Combined sources16
Beta strandi123 – 127Combined sources5
Beta strandi130 – 133Combined sources4
Helixi135 – 141Combined sources7
Helixi150 – 158Combined sources9
Turni174 – 177Combined sources4
Helixi186 – 190Combined sources5
Turni195 – 199Combined sources5
Helixi214 – 229Combined sources16
Helixi241 – 244Combined sources4
Helixi252 – 256Combined sources5
Helixi262 – 277Combined sources16
Helixi284 – 287Combined sources4
Helixi288 – 300Combined sources13
Turni304 – 307Combined sources4
Helixi324 – 332Combined sources9
Helixi338 – 350Combined sources13
Helixi355 – 365Combined sources11
Turni366 – 370Combined sources5
Helixi374 – 384Combined sources11
Helixi390 – 400Combined sources11
Helixi417 – 422Combined sources6
Helixi427 – 432Combined sources6
Helixi434 – 436Combined sources3
Turni441 – 445Combined sources5
Helixi447 – 449Combined sources3
Helixi452 – 457Combined sources6
Turni462 – 464Combined sources3
Helixi473 – 487Combined sources15

3D structure databases

Select the link destinations:
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum

Family & Domainsi

Domains and Repeats

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


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

Sequence similaritiesi

Belongs to the DNA photolyase class-1 family.Curated

Phylogenomic databases

eggNOGiKOG0133. Eukaryota.
COG0415. LUCA.

Family and domain databases

Gene3Di3.40.50.620. 1 hit.
InterProiView protein in InterPro
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 statusi: Complete.

P97784-1 [UniParc]FASTAAdd to basket

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Mass (Da):68,001
Last modified:May 1, 1997 - v1

Sequence databases

Select the link destinations:
Links Updated
AB000777 mRNA. Translation: BAA19175.1.
AF156986 mRNA. Translation: AAD39548.1.
AK162460 mRNA. Translation: BAE36931.1.
BC022174 mRNA. Translation: AAH22174.1.
BC085499 mRNA. Translation: AAH85499.1.
RefSeqiNP_031797.1. NM_007771.3.

Genome annotation databases

EnsembliENSMUST00000020227; ENSMUSP00000020227; ENSMUSG00000020038.
UCSCiuc007gle.1. mouse.

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.

Entry informationi

Entry nameiCRY1_MOUSE
AccessioniPrimary (citable) accession number: P97784
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: May 1, 1997
Last modified: June 7, 2017
This is version 144 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome


  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families