Tbio CLOCK Circadian locomoter output cycles protein kaput

Protein Summary

Description

Transcriptional activator 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. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Uniprot Accession IDs

• O15516
• A0AV01
• A2I2N9
• O14516
• Q9UIT8
• hCLOCK

Gene Name

• CLOCK

Ensembl ID

• ENST00000309964
• ENSP00000308741
• ENSG00000134852
• ENST00000381322
• ENSP00000370723
• ENST00000513440
• ENSP00000426983

Symbol

• BHLHE8
• KIAA0334
• KAT13D
• bHLHe8

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	1
biological process	0.98
co-expressed gene	0.89
cell type or tissue	0.85
microRNA	0.84

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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: 618.62   (req: < 5)

Gene RIFs: 173   (req: <= 3)

Antibodies: 450   (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: 618.62   (req: >= 5)

Gene RIFs: 173   (req: > 3)

Antibodies: 450   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 32

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

GWAS Traits (14)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
waist-hip ratio	EFO_0004343	3	14	15		94.9
BMI-adjusted waist-hip ratio	EFO_0007788	4	13	15		94.4
hip circumference	EFO_0005093	1	7	7		86.8
BMI-adjusted hip circumference	EFO_0008039	2	11	11		81.7
waist circumference	EFO_0004342	1	2	2		63.9

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
waist-hip ratio	EFO_0004343	15		94.9
BMI-adjusted waist-hip ratio	EFO_0007788	15		94.4
hip circumference	EFO_0005093	7		86.8
BMI-adjusted hip circumference	EFO_0008039	11		81.7
waist circumference	EFO_0004342	2		63.9

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Orthologs (9)

1 – 5 of 9

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Mouse	circadian locomotor output cycles kaput	MGI:99698	12753
Rat	clock circadian regulator	RGD:620271	60447
Dog	clock circadian regulator	VGNC:39353	475145
Horse	clock circadian regulator	VGNC:16627	100034166
Cow	clock circadian regulator	VGNC:27456	100300400

Species	Name	OMA	EggNOG	Inparanoid
Mouse	circadian locomotor output cycles kaput
Rat	clock circadian regulator
Dog	clock circadian regulator
Horse	clock circadian regulator
Cow	clock circadian regulator

Protein Structure (1 Structure, 1 AlphaFold Model)

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Representation

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  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

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More information can be found at RCSB PDB

AF-O15516-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 1 of 1

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (16)

Reactome (9)

KEGG (2)

PathwayCommons (2)

WikiPathways (3)

BMAL1:CLOCK,NPAS2 activates circadian gene expression (R-HSA-1368108)

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Find Similar Targets

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	BMAL1:CLOCK,NPAS2 activates circadian gene expression	27 targets	R-HSA-1368108
Reactome	Chromatin modifying enzymes	238 targets	R-HSA-3247509
Reactome	Chromatin organization	238 targets	R-HSA-4839726
Reactome	Circadian Clock	69 targets	R-HSA-400253
Reactome	HATs acetylate histones	107 targets	R-HSA-3214847

Name	Explore in Pharos	Explore in Source
BMAL1:CLOCK,NPAS2 activates circadian gene expression	27 targets	R-HSA-1368108
Chromatin modifying enzymes	238 targets	R-HSA-3247509
Chromatin organization	238 targets	R-HSA-4839726
Circadian Clock	69 targets	R-HSA-400253
HATs acetylate histones	107 targets	R-HSA-3214847

Gene Ontology Terms (39)

Functions (11)

Components (7)

Processes (21)

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GO Term	Evidence	Assigned by
DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
E-box binding	Inferred from Direct Assay (IDA)	UniProtKB
RNA polymerase II proximal promoter sequence-specific DNA binding	Inferred from Direct Assay (IDA)	BHF-UCL
histone acetyltransferase activity	Inferred from Mutant Phenotype (IMP)	UniProtKB
chromatin DNA binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
DNA-binding transcription activator activity, RNA polymerase II-specific	Inferred from Sequence or structural Similarity (ISS)	BHF-UCL
DNA-binding transcription factor activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
DNA-binding transcription factor activity, RNA polymerase II-specific	Inferred from Sequence or structural Similarity (ISS)	BHF-UCL
RNA polymerase II distal enhancer sequence-specific DNA binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
sequence-specific DNA binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB

Protein-Protein Interactions (145)

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1 – 10 of 145

• See Interactions on String-DB

ARNTL2

Tbio

Family:  TF

Novelty:  0.0039351

p_int:  0.99999995

p_ni:  5e-8

Score:  0.977

Data Source:  BioPlex,Reactome,STRINGDB

ARNTL

Tbio

Family:  TF

Novelty:  0.00102829

p_int:  0.999999503

p_ni:  4.97e-7

Score:  0.999

Data Source:  BioPlex,Reactome,STRINGDB

CIPC

Tdark

Novelty:  0.02263148

p_int:  0.999998242

p_ni:  0.000001757

p_wrong:  2e-9

Score:  0.984

Data Source:  BioPlex,STRINGDB

EXOC1

Tbio

Novelty:  0.01073858

p_int:  0.999995492

p_ni:  0.000004488

p_wrong:  2e-8

Score:  0.217

Data Source:  BioPlex,STRINGDB

TEKT4

Tbio

Novelty:  0.05559086

p_int:  0.999683425

p_ni:  0.000249772

p_wrong:  0.000066803

Score:  0.211

Data Source:  BioPlex,STRINGDB

SRGAP3

Tbio

Family:  Enzyme

Novelty:  0.01913784

p_int:  0.999531401

p_ni:  0.000434

p_wrong:  0.0000346

Score:  0.282

Data Source:  BioPlex,STRINGDB

CRY1

Tchem

Novelty:  0.00116593

Score:  0.999

Data Source:  Reactome,STRINGDB

CRY2

Tbio

Novelty:  0.00156961

Score:  0.999

Data Source:  Reactome,STRINGDB

CSNK1E

Tclin

Family:  Kinase

Novelty:  0.00891859

Score:  0.997

Data Source:  Reactome,STRINGDB

BHLHE41

Tbio

Family:  TF

Novelty:  0.01015053

Score:  0.994

Data Source:  STRINGDB

Publication Statistics

PubMed Score  618.62

PubMed score by year

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PubTator Score  486.85

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

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3D-structure
Activator
Acyltransferase
Biological rhythms
Complete proteome
Cytoplasm
DNA damage
DNA-binding
Isopeptide bond
Nucleus

GWAS Trait Find Similar Targets

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albuminuria
balding measurement
BMI-adjusted hip circumference
BMI-adjusted waist circumference
BMI-adjusted waist-hip ratio
body height
coronary artery disease
hip circumference
lymphocyte count
neutrophil percentage of leukocytes

MGI Phenotype Find Similar Targets

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adipose tissue phenotype
behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
digestive/alimentary phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
homeostasis/metabolism phenotype
integument phenotype
liver/biliary system phenotype