Tbio CRY2 Cryptochrome-2

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. 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). 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]

Uniprot Accession IDs

• Q49AN0
• B4DH32
• B4DZD6
• O75148
• Q8IV71

Gene Name

• CRY2

Ensembl ID

• ENST00000417225
• ENSP00000397419
• ENSG00000121671
• ENST00000616080
• ENSP00000484684

Symbol

• KIAA0658
• HCRY2
• PHLL2

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	0.99
biological process	0.9
virus perturbation	0.85
transcription factor binding site profile	0.74
microRNA	0.71

Protein Classes

PANTHER Classes

Protein / Nucleic Acid Binding / Dna Binding Protein / Dna Photolyase / Cryptochrome-2

Protein / Lyase / Cryptochrome-2

DTO Classes

Protein / Enzyme / Lyase / Dna Photolyase / Cryptochrome-2

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: 672.54   (req: < 5)

Gene RIFs: 51   (req: <= 3)

Antibodies: 223   (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: 672.54   (req: >= 5)

Gene RIFs: 51   (req: > 3)

Antibodies: 223   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 21

Tchem

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

Active Ligand: 0

Tclin

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

Active Drug: 0

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Expression Data (0 Tissues)

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Target Illumination GWAS Analytics (TIGA)

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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 (0)

No active ligands found

Protein-Protein Interactions (104)

Explore Interacting Targets

1 – 10 of 104

• See Interactions on String-DB

CRY1

Tchem

Novelty:  0.00116593

p_int:  0.999999999

p_wrong:  1e-9

Score:  0.996

Data Source:  BioPlex,STRINGDB

OTUD4

Tbio

Novelty:  0.17121119

p_int:  0.999997964

p_ni:  0.000002036

Data Source:  BioPlex

SKP1

Tbio

Family:  Enzyme

Novelty:  0.00149739

p_int:  0.99998511

p_ni:  0.00001489

Score:  0.545

Data Source:  BioPlex,STRINGDB

PER1

Tbio

Novelty:  0.01290576

p_int:  0.999984285

p_ni:  0.000015715

Score:  0.998

Data Source:  BioPlex,Reactome,STRINGDB

CSNK1D

Tchem

Family:  Kinase

Novelty:  0.00896935

p_int:  0.999982271

p_ni:  0.000017729

Score:  0.994

Data Source:  BioPlex,STRINGDB

TEKT4

Tbio

Novelty:  0.05559086

p_int:  0.99998127

p_ni:  0.000018725

p_wrong:  5e-9

Score:  0.71

Data Source:  BioPlex,STRINGDB

FBXL3

Tbio

Novelty:  0.05042679

p_int:  0.999950282

p_ni:  0.000049718

Score:  0.99

Data Source:  BioPlex,Reactome,STRINGDB

AP2M1

Tbio

Novelty:  0.00769368

p_int:  0.999884224

p_ni:  0.000115773

p_wrong:  3e-9

Data Source:  BioPlex

QPRT

Tbio

Family:  Enzyme

Novelty:  0.00781554

p_int:  0.999258559

p_ni:  0.00074081

p_wrong:  6.31e-7

Score:  0.305

Data Source:  BioPlex,STRINGDB

SERTAD4

Tdark

Novelty:  0.70786986

p_int:  0.999146985

p_ni:  0.000001682

p_wrong:  0.000851333

Data Source:  BioPlex

Nearest Tclin Targets

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

Pathways (23)

Reactome (1)

KEGG (1)

PathwayCommons (2)

WikiPathways (19)

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 (25)

Functions (7)

Components (4)

Processes (14)

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1 – 7 of 7

GO Term	Evidence	Assigned by
damaged DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
single-stranded DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
phosphatase binding	Inferred from Physical Interaction (IPI)	UniProtKB
FAD binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
transcription regulatory region sequence-specific DNA binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
blue light photoreceptor activity	Non-traceable Author Statement (NAS)	UniProtKB

Disease Associations ()

No disease associations found

GWAS Traits (11)

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5

1 – 5 of 11

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
glucose measurement	EFO_0004468	2	2	2		91.9
high density lipoprotein cholesterol measurement	EFO_0004612	3	2	3		87.5
fasting blood glucose measurement	EFO_0004465	6	1	6		77.9
type II diabetes mellitus	EFO_0001360	3	3	2	1	71.4
body mass index	EFO_0004340	1	1	1		63.7

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 11

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
glucose measurement	EFO_0004468	2		91.9
high density lipoprotein cholesterol measurement	EFO_0004612	3		87.5
fasting blood glucose measurement	EFO_0004465	6		77.9
type II diabetes mellitus	EFO_0001360	2	1	71.4
body mass index	EFO_0004340	1		63.7

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UniProt Keyword Find Similar Targets

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

GWAS Trait Find Similar Targets

No Header	No Header
body height
body mass index
fasting blood glucose measurement
glucose measurement
high density lipoprotein cholesterol measurement
mean corpuscular hemoglobin concentration
sex hormone-binding globulin measurement
smoking status measurement
triglyceride measurement
type II diabetes mellitus

MGI Phenotype Find Similar Targets

No Header	No Header
behavior/neurological phenotype
hematopoietic system phenotype
immune system phenotype
skeleton 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 2	VGNC:3142	742186
Macaque	cryptochrome circadian regulator 2		715000
Mouse	cryptochrome 2 (photolyase-like)	MGI:1270859	12953
Rat	cryptochrome circadian regulator 2	RGD:620935	170917
Dog	cryptochrome circadian regulator 2	VGNC:39634	483641

Species	Name	OMA	EggNOG	Inparanoid
Chimp	cryptochrome circadian regulator 2
Macaque	cryptochrome circadian regulator 2
Mouse	cryptochrome 2 (photolyase-like)
Rat	cryptochrome circadian regulator 2
Dog	cryptochrome circadian regulator 2

Publication Statistics

PubMed Score 672.54

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PubTator Score 125.96

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Related Publications

Text Mined References (90)

GeneRif Annotations (51)

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PMID	Year	Title