Tchem CRY1 Cryptochrome-1

Protein Summary

Description

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. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that downregulates gluconeogenic gene expression (By similarity). 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. This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been associated with altered sleep patterns. The encoded protein is widely conserved across plants and animals. Loss of the related gene in mouse results in a shortened circadian cycle in complete darkness. [provided by RefSeq, Jan 2014]

Uniprot Accession IDs

• Q16526

Gene Name

• CRY1

Ensembl ID

• ENST00000008527
• ENSP00000008527
• ENSG00000008405

Symbol

• PHLL1
• DSPD
• PHLL1

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	1
biological process	0.98
transcription factor binding site profile	0.9
kinase perturbation	0.71
cellular component	0.65

Protein Classes

PANTHER Classes

Protein / Nucleic Acid Binding / Dna Binding Protein / Dna Photolyase / Cryptochrome-1

Protein / Lyase / Cryptochrome-1

DTO Classes

Protein / Enzyme / Lyase / Dna Photolyase / Cryptochrome-1

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 897.43   (req: < 5)

Gene RIFs: 49   (req: <= 3)

Antibodies: 255   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 897.43   (req: >= 5)

Gene RIFs: 49   (req: > 3)

Antibodies: 255   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 29

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 1

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

Expression Data (0 Tissues)

tutorial

No expression data found

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Related Tools (4)

Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (0)

No approved drugs found

Active Ligands (1)

Explore Active Ligands

1 – 1 of 1

KL044

CRY1Tchem

pEC50 : 7.2

Protein-Protein Interactions (109)

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1 – 10 of 109

• See Interactions on String-DB

CRY2

Tbio

Novelty:  0.00156961

p_int:  0.999999999

p_wrong:  1e-9

Score:  0.996

Data Source:  BioPlex,STRINGDB

FBXL3

Tbio

Novelty:  0.05042679

p_int:  0.999999998

p_ni:  2e-9

Score:  0.99

Data Source:  BioPlex,Reactome,STRINGDB

PER1

Tbio

Novelty:  0.01290576

p_int:  0.999999986

p_ni:  1.4e-8

Score:  0.999

Data Source:  BioPlex,Reactome,STRINGDB

CSNK1E

Tclin

Family:  Kinase

Novelty:  0.00891859

p_int:  0.999999606

p_ni:  3.94e-7

Score:  0.998

Data Source:  BioPlex,Reactome,STRINGDB

RGS20

Tbio

Novelty:  0.04087618

p_int:  0.999998002

p_ni:  0.000001997

p_wrong:  1e-9

Score:  0.182

Data Source:  BioPlex,STRINGDB

SKP1

Tbio

Family:  Enzyme

Novelty:  0.00149739

p_int:  0.99999407

p_ni:  0.00000593

Score:  0.563

Data Source:  BioPlex,STRINGDB

TEKT4

Tbio

Novelty:  0.05559086

p_int:  0.999990895

p_ni:  0.000009105

Score:  0.552

Data Source:  BioPlex,STRINGDB

RETNLB

Tbio

Novelty:  0.00777842

p_int:  0.999990451

p_ni:  0.000009525

p_wrong:  2.4e-8

Data Source:  BioPlex

CSNK1D

Tchem

Family:  Kinase

Novelty:  0.00896935

p_int:  0.999979755

p_ni:  0.000020245

Score:  0.993

Data Source:  BioPlex,STRINGDB

AP2M1

Tbio

Novelty:  0.00769368

p_int:  0.999956739

p_ni:  0.00004326

p_wrong:  1e-9

Score:  0.201

Data Source:  BioPlex,STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (7)

Reactome (1)

KEGG (1)

PathwayCommons (2)

WikiPathways (3)

Circadian Clock (R-HSA-400253)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Circadian Clock	69 targets	R-HSA-400253

Name	Explore in Pharos	Explore in Source
Circadian Clock	69 targets	R-HSA-400253

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (31)

Functions (9)

Components (2)

Processes (20)

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GO Term	Evidence	Assigned by
double-stranded DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
nuclear hormone receptor binding	Inferred from Physical Interaction (IPI)	UniProtKB
phosphatase binding	Inferred from Physical Interaction (IPI)	UniProtKB
DNA binding	Traceable Author Statement (TAS)	ProtInc
blue light photoreceptor activity	Non-traceable Author Statement (NAS)	UniProtKB
E-box binding	Inferred from Electronic Annotation (IEA)	Ensembl
histone deacetylase binding	Inferred from Electronic Annotation (IEA)	Ensembl
nucleotide binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW
protein kinase binding	Inferred from Electronic Annotation (IEA)	Ensembl

Disease Associations (null)

No disease associations found

GWAS Traits (10)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
alkaline phosphatase measurement	EFO_0004533	2	2	1	8.6	80.2
chronotype measurement	EFO_0008328	3	2	2	1	71.1
bone density	EFO_0003923	1	2	2		58.2
heel bone mineral density	EFO_0009270	2	2	2		52.7
femoral neck bone mineral density	EFO_0007785	1	1	1		35

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 10

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
alkaline phosphatase measurement	EFO_0004533	1	8.6	80.2
chronotype measurement	EFO_0008328	2	1	71.1
bone density	EFO_0003923	2		58.2
heel bone mineral density	EFO_0009270	2		52.7
femoral neck bone mineral density	EFO_0007785	1		35

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UniProt Keyword Find Similar Targets

No Header	No Header
Biological rhythms
Chromophore
Complete proteome
Cytoplasm
FAD
Flavoprotein
Isopeptide bond
Nucleotide-binding
Nucleus
Phosphoprotein

GWAS Trait Find Similar Targets

No Header	No Header
alkaline phosphatase measurement
BMI-adjusted hip circumference
BMI-adjusted waist-hip ratio
body height
bone density
chronotype measurement
femoral neck bone mineral density
heel bone mineral density
influenza A (H1N1)
waist-hip ratio

MGI Phenotype Find Similar Targets

No Header	No Header
behavior/neurological phenotype

IDG Resources

No IDG generated resources found

Orthologs (13)

1 – 5 of 13

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	cryptochrome circadian regulator 1	VGNC:5348	452205
Macaque	cryptochrome circadian regulator 1		703752
Mouse	cryptochrome 1 (photolyase-like)	MGI:1270841	12952
Rat	cryptochrome circadian regulator 1	RGD:735083	299691
Dog	cryptochrome circadian regulator 1	VGNC:39633	474528

Species	Name	OMA	EggNOG	Inparanoid
Chimp	cryptochrome circadian regulator 1
Macaque	cryptochrome circadian regulator 1
Mouse	cryptochrome 1 (photolyase-like)
Rat	cryptochrome circadian regulator 1
Dog	cryptochrome circadian regulator 1

Publication Statistics

PubMed Score 897.43

PubMed score by year

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PubTator Score 165.83

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Related Publications

Text Mined References (83)

GeneRif Annotations (49)

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PMID	Year	Title