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O15516

- CLOCK_HUMAN

UniProt

O15516 - CLOCK_HUMAN

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Protein
Circadian locomoter output cycles protein kaput
Gene
CLOCK, BHLHE8, KIAA0334
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. 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 and also genes implicated in glucose and lipid metabolism. 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. 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/DEC1.7 Publications

Catalytic activityi

Acetyl-CoA + [histone] = CoA + acetyl-[histone].

Enzyme regulationi

The redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer.

GO - Molecular functioni

  1. DNA binding Source: UniProtKB
  2. E-box binding Source: UniProtKB
  3. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: BHF-UCL
  4. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  5. RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription Source: BHF-UCL
  6. chromatin DNA binding Source: UniProtKB
  7. core promoter binding Source: UniProtKB
  8. histone acetyltransferase activity Source: UniProtKB
  9. protein binding Source: UniProtKB
  10. sequence-specific DNA binding Source: UniProtKB
  11. sequence-specific DNA binding transcription factor activity Source: UniProtKB
  12. signal transducer activity Source: InterPro

GO - Biological processi

  1. DNA damage checkpoint Source: UniProtKB
  2. cellular response to ionizing radiation Source: UniProtKB
  3. chromatin organization Source: Reactome
  4. circadian regulation of gene expression Source: UniProtKB
  5. circadian rhythm Source: ProtInc
  6. histone acetylation Source: GOC
  7. negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
  8. negative regulation of transcription, DNA-templated Source: UniProtKB
  9. photoperiodism Source: ProtInc
  10. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  11. positive regulation of transcription from RNA polymerase II promoter Source: MGI
  12. positive regulation of transcription, DNA-templated Source: UniProtKB
  13. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  14. regulation of hair cycle Source: UniProtKB
  15. regulation of insulin secretion Source: UniProtKB
  16. regulation of transcription from RNA polymerase II promoter Source: ProtInc
  17. regulation of transcription, DNA-templated Source: UniProtKB
  18. regulation of type B pancreatic cell development Source: UniProtKB
  19. response to redox state Source: UniProtKB
  20. signal transduction Source: ProtInc
  21. spermatogenesis Source: UniProtKB
  22. transcription from RNA polymerase II promoter Source: GOC
Complete GO annotation...

Keywords - Molecular functioni

Activator, Acyltransferase, Transferase

Keywords - Biological processi

Biological rhythms, DNA damage, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
REACT_116145. PPARA activates gene expression.
REACT_118659. RORA activates circadian gene expression.
REACT_118789. REV-ERBA represses gene expression.
REACT_172610. HATs acetylate histones.
REACT_24941. Circadian Clock.

Names & Taxonomyi

Protein namesi
Recommended name:
Circadian locomoter output cycles protein kaput (EC:2.3.1.48)
Short name:
hCLOCK
Alternative name(s):
Class E basic helix-loop-helix protein 8
Short name:
bHLHe8
Gene namesi
Name:CLOCK
Synonyms:BHLHE8, KIAA0334
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 4

Organism-specific databases

HGNCiHGNC:2082. CLOCK.

Subcellular locationi

Nucleus. Chromosome. Cytoplasm By similarity
Note: Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1-dependent. Phosphorylated form located in the nucleus while the nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2 By similarity. Localizes to sites of DNA damage in a H2AX-independent manner.3 Publications

GO - Cellular componenti

  1. chromatoid body Source: UniProtKB
  2. chromosome Source: UniProtKB
  3. cytosol Source: Reactome
  4. intracellular membrane-bounded organelle Source: HPA
  5. nucleus Source: UniProtKB
  6. transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Chromosome, Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi116 – 1161E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with K-367 and L-601. 1 Publication
Mutagenesisi332 – 3321G → E: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with L-840. 1 Publication
Mutagenesisi360 – 3601H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity. 1 Publication
Mutagenesisi367 – 3671E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with E-116 and L-601. 1 Publication
Mutagenesisi451 – 4511T → F: Significant loss in phosphorylation. 1 Publication
Mutagenesisi461 – 4611T → F: Significant loss in phosphorylation. 1 Publication
Mutagenesisi601 – 6011V → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with K-116 and K-367. 1 Publication
Mutagenesisi840 – 8401P → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with E-332. 1 Publication

Organism-specific databases

PharmGKBiPA26609.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 846846Circadian locomoter output cycles protein kaput
PRO_0000127163Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei38 – 381Phosphoserine By similarity
Modified residuei42 – 421Phosphoserine By similarity
Cross-linki67 – 67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)
Modified residuei408 – 4081Phosphoserine By similarity
Modified residuei427 – 4271Phosphoserine; by GSK3-beta By similarity
Modified residuei451 – 4511Phosphothreonine; by CDK51 Publication
Modified residuei461 – 4611Phosphothreonine; by CDK51 Publication
Cross-linki842 – 842Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity

Post-translational modificationi

Ubiquitinated, leading to its proteasomal degradation By similarity.
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2 By similarity.
Phosphorylation is dependent on the CLOCK-ARNTL/BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver. May be phosphorylated by CSNK1D and CKSN1E.1 Publication
Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity. Sumoylation stimulates cell proliferation and increases the proportion of S phase cells in breast cancer cell lines.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO15516.
PaxDbiO15516.
PRIDEiO15516.

PTM databases

PhosphoSiteiO15516.

Expressioni

Tissue specificityi

Hair follicles (at protein level). Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in testis and skeletal muscle. Low levels in thymus, lung and liver. Expressed in all brain regions with highest levels in cerebellum. Highly expressed in the suprachiasmatic nucleus (SCN).2 Publications

Gene expression databases

ArrayExpressiO15516.
BgeeiO15516.
CleanExiHS_CLOCK.
GenevestigatoriO15516.

Organism-specific databases

HPAiHPA001867.
HPA027565.

Interactioni

Subunit structurei

Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with ARNTL/BMAL1 and this heterodimerization is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and ARNTL/BMAL1. Interacts with PER1, PER2 and CRY1. Interaction with PER and CRY proteins requires translocation to the nucleus. Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA. Interacts with CIPC. Interacts with NR3C1 in a ligand-dependent fashion. Interacts with RELA/p65, EIF4E, PIWIL1, DDX4 and MGEA5. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with ESR1 and estrogen stimulates this interaction. Interacts with the complex p35/CDK5. Interacts with KAT2B, CREBBP and EP300. Interacts with ID1, ID2 and ID3.5 Publications

Protein-protein interaction databases

BioGridi114944. 16 interactions.
IntActiO15516. 3 interactions.
STRINGi9606.ENSP00000308741.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi33 – 5826
Beta strandi61 – 633
Helixi70 – 8920

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4H10X-ray2.40B29-89[»]
ProteinModelPortaliO15516.
SMRiO15516. Positions 31-444.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini34 – 8451bHLH
Add
BLAST
Domaini107 – 17771PAS 1
Add
BLAST
Domaini262 – 33271PAS 2
Add
BLAST
Domaini336 – 37944PAC
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni371 – 845475Interaction with NR3C1 By similarity
Add
BLAST
Regioni514 – 56451Implicated in the circadian rhythmicity By similarity
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi32 – 4716Nuclear localization signal By similarity
Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi744 – 76017Gln-rich
Add
BLAST
Compositional biasi819 – 82810Poly-Gln

Sequence similaritiesi

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiNOG300360.
HOGENOMiHOG000234382.
HOVERGENiHBG050997.
InParanoidiO15516.
KOiK02223.
OMAiTPINMQG.
OrthoDBiEOG71G9T7.
PhylomeDBiO15516.
TreeFamiTF324568.

Family and domain databases

Gene3Di4.10.280.10. 1 hit.
InterProiIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamiPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSiPR00785. NCTRNSLOCATR.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O15516-1 [UniParc]FASTAAdd to Basket

« Hide

MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF    50
NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW 100
KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV 150
DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG 200
TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT HRPSYEDRVC 250
FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 300
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW 350
LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA 400
DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS 450
TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS 500
QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK 550
IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 600
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP 650
SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ 700
IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT 750
LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL 800
ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ 846
Length:846
Mass (Da):95,304
Last modified:January 1, 1998 - v1
Checksum:iC292B451A33E4CBF
GO

Sequence cautioni

The sequence BAA20792.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti208 – 2081S → C.
Corresponds to variant rs34897046 [ dbSNP | Ensembl ].
VAR_040061
Natural varianti380 – 3801E → K.
Corresponds to variant rs1056478 [ dbSNP | Ensembl ].
VAR_040062
Natural varianti395 – 3951L → I.
Corresponds to variant rs6855837 [ dbSNP | Ensembl ].
VAR_029076
Natural varianti542 – 5421H → R.
Corresponds to variant rs3762836 [ dbSNP | Ensembl ].
VAR_029077

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti440 – 4401S → P in AAF13733. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF011568 mRNA. Translation: AAB83969.1.
AH008440 Genomic DNA. Translation: AAF13733.1.
EF015897 Genomic DNA. Translation: ABM64208.1.
AB002332 mRNA. Translation: BAA20792.2. Different initiation.
AK291708 mRNA. Translation: BAF84397.1.
BC126157 mRNA. Translation: AAI26158.1.
BC126159 mRNA. Translation: AAI26160.1.
AB005535 mRNA. Translation: BAA21774.1.
CCDSiCCDS3500.1.
RefSeqiNP_001254772.1. NM_001267843.1.
NP_004889.1. NM_004898.3.
XP_005265844.1. XM_005265787.1.
XP_006714117.1. XM_006714054.1.
UniGeneiHs.436975.
Hs.689578.

Genome annotation databases

EnsembliENST00000309964; ENSP00000308741; ENSG00000134852.
ENST00000381322; ENSP00000370723; ENSG00000134852.
ENST00000513440; ENSP00000426983; ENSG00000134852.
GeneIDi9575.
KEGGihsa:9575.
UCSCiuc003haz.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF011568 mRNA. Translation: AAB83969.1 .
AH008440 Genomic DNA. Translation: AAF13733.1 .
EF015897 Genomic DNA. Translation: ABM64208.1 .
AB002332 mRNA. Translation: BAA20792.2 . Different initiation.
AK291708 mRNA. Translation: BAF84397.1 .
BC126157 mRNA. Translation: AAI26158.1 .
BC126159 mRNA. Translation: AAI26160.1 .
AB005535 mRNA. Translation: BAA21774.1 .
CCDSi CCDS3500.1.
RefSeqi NP_001254772.1. NM_001267843.1.
NP_004889.1. NM_004898.3.
XP_005265844.1. XM_005265787.1.
XP_006714117.1. XM_006714054.1.
UniGenei Hs.436975.
Hs.689578.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
4H10 X-ray 2.40 B 29-89 [» ]
ProteinModelPortali O15516.
SMRi O15516. Positions 31-444.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 114944. 16 interactions.
IntActi O15516. 3 interactions.
STRINGi 9606.ENSP00000308741.

PTM databases

PhosphoSitei O15516.

Proteomic databases

MaxQBi O15516.
PaxDbi O15516.
PRIDEi O15516.

Protocols and materials databases

DNASUi 9575.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000309964 ; ENSP00000308741 ; ENSG00000134852 .
ENST00000381322 ; ENSP00000370723 ; ENSG00000134852 .
ENST00000513440 ; ENSP00000426983 ; ENSG00000134852 .
GeneIDi 9575.
KEGGi hsa:9575.
UCSCi uc003haz.2. human.

Organism-specific databases

CTDi 9575.
GeneCardsi GC04M056294.
HGNCi HGNC:2082. CLOCK.
HPAi HPA001867.
HPA027565.
MIMi 601851. gene.
neXtProti NX_O15516.
PharmGKBi PA26609.
HUGEi Search...
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG300360.
HOGENOMi HOG000234382.
HOVERGENi HBG050997.
InParanoidi O15516.
KOi K02223.
OMAi TPINMQG.
OrthoDBi EOG71G9T7.
PhylomeDBi O15516.
TreeFami TF324568.

Enzyme and pathway databases

Reactomei REACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
REACT_116145. PPARA activates gene expression.
REACT_118659. RORA activates circadian gene expression.
REACT_118789. REV-ERBA represses gene expression.
REACT_172610. HATs acetylate histones.
REACT_24941. Circadian Clock.

Miscellaneous databases

GeneWikii CLOCK.
GenomeRNAii 9575.
NextBioi 35907.
PROi O15516.
SOURCEi Search...

Gene expression databases

ArrayExpressi O15516.
Bgeei O15516.
CleanExi HS_CLOCK.
Genevestigatori O15516.

Family and domain databases

Gene3Di 4.10.280.10. 1 hit.
InterProi IPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view ]
Pfami PF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view ]
PRINTSi PR00785. NCTRNSLOCATR.
SMARTi SM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view ]
SUPFAMi SSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
PROSITEi PS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei."
    Steeves T.D.L., King D.P., Zhao Y., Sangoram A.M., Du F., Bowcock A.M., Moore R.Y., Takahashi J.S.
    Genomics 57:189-200(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], TISSUE SPECIFICITY.
  2. NHLBI resequencing and genotyping service (RS&G)
    Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  3. "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."
    Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
    DNA Res. 4:141-150(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain.
  4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Placenta.
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Lung.
  6. "Molecular cloning of human Clock cDNA 5'-end."
    Ikeda M., Takehara N., Ebisawa T., Yamauchi T., Nomura M.
    Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-349.
    Tissue: Brain.
  7. "Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors."
    Rutter J., Reick M., Wu L.C., McKnight S.L.
    Science 293:510-514(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING.
  8. "Histone acetyltransferase-dependent chromatin remodeling and the vascular clock."
    Curtis A.M., Seo S.B., Westgate E.J., Rudic R.D., Smyth E.M., Chakravarti D., FitzGerald G.A., McNamara P.
    J. Biol. Chem. 279:7091-7097(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KAT2B; CREBBP AND EP300.
  9. Cited for: MUTAGENESIS OF GLU-116; GLY-332; HIS-360; GLU-367; VAL-601 AND PRO-840.
  10. "CLOCK/BMAL1 regulates human nocturnin transcription through binding to the E-box of nocturnin promoter."
    Li R., Yue J., Zhang Y., Zhou L., Hao W., Yuan J., Qiang B., Ding J.M., Peng X., Cao J.M.
    Mol. Cell. Biochem. 317:169-177(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  11. "The transcriptional repressor ID2 can interact with the canonical clock components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 expression."
    Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.
    J. Biol. Chem. 285:38987-39000(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ID2.
  12. "Biochemical analysis of the canonical model for the mammalian circadian clock."
    Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.
    J. Biol. Chem. 286:25891-25902(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ARNTL; CRY1 AND PER2.
  13. "Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man."
    Charmandari E., Chrousos G.P., Lambrou G.I., Pavlaki A., Koide H., Ng S.S., Kino T.
    PLoS ONE 6:E25612-E25612(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH NR3C1.
  14. "A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling."
    Cotta-Ramusino C., McDonald E.R. III, Hurov K., Sowa M.E., Harper J.W., Elledge S.J.
    Science 332:1313-1317(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  15. "Diurnal expression of the thrombopoietin gene is regulated by CLOCK."
    Tracey C.J., Pan X., Catterson J.H., Harmar A.J., Hussain M.M., Hartley P.S.
    J. Thromb. Haemost. 10:662-669(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  16. "Mechanism of the circadian clock in physiology."
    Richards J., Gumz M.L.
    Am. J. Physiol. 304:R1053-R1064(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  17. "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation."
    Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H., Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.
    J. Biol. Chem. 288:36878-36889(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-451 AND THR-461, MUTAGENESIS OF THR-451 AND THR-461, INTERACTION WITH THE COMPLEX P35/CDK5.
  18. "p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks."
    Baeza-Raja B., Eckel-Mahan K., Zhang L., Vagena E., Tsigelny I.F., Sassone-Corsi P., Ptacek L.J., Akassoglou K.
    J. Neurosci. 33:10221-10234(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  19. "CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-alpha."
    Li S., Wang M., Ao X., Chang A.K., Yang C., Zhao F., Bi H., Liu Y., Xiao L., Wu H.
    Oncogene 32:4883-4891(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUMOYLATION, SUBCELLULAR LOCATION, INTERACTION WITH ESR1.
  20. "Metabolism and the circadian clock converge."
    Eckel-Mahan K., Sassone-Corsi P.
    Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  21. "A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock."
    Al-Nuaimi Y., Hardman J.A., Biro T., Haslam I.S., Philpott M.P., Toth B.I., Farjo N., Farjo B., Baier G., Watson R.E., Grimaldi B., Kloepper J.E., Paus R.
    J. Invest. Dermatol. 134:610-619(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY.
  22. "Molecular architecture of the mammalian circadian clock."
    Partch C.L., Green C.B., Takahashi J.S.
    Trends Cell Biol. 24:90-99(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.

Entry informationi

Entry nameiCLOCK_HUMAN
AccessioniPrimary (citable) accession number: O15516
Secondary accession number(s): A0AV01
, A2I2N9, O14516, Q9UIT8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 1, 1998
Last modified: September 3, 2014
This is version 148 of the entry and version 1 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

Miscellaneous

CLOCK-ARNTL/BMAL1 double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-ARNTL/BMAl1 transcriptional activity of PER1 and disrupt circadian rhythmicity.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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