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O15516 (CLOCK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 147. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Circadian locomoter output cycles protein kaput

Short name=hCLOCK
EC=2.3.1.48
Alternative name(s):
Class E basic helix-loop-helix protein 8
Short name=bHLHe8
Gene names
Name:CLOCK
Synonyms:BHLHE8, KIAA0334
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length846 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.8 Ref.10 Ref.12 Ref.13 Ref.14 Ref.17 Ref.20

Catalytic activity

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

Enzyme regulation

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.

Subunit structure

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. Ref.8 Ref.11 Ref.12 Ref.16 Ref.18

Subcellular location

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 By similarity. Localizes to sites of DNA damage in a H2AX-independent manner. Ref.8 Ref.13 Ref.18

Tissue specificity

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). Ref.1 Ref.20

Post-translational modification

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. Ref.16

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. Ref.18

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.

Sequence similarities

Contains 1 bHLH (basic helix-loop-helix) domain.

Contains 1 PAC (PAS-associated C-terminal) domain.

Contains 2 PAS (PER-ARNT-SIM) domains.

Sequence caution

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

Ontologies

Keywords
   Biological processBiological rhythms
DNA damage
Transcription
Transcription regulation
   Cellular componentChromosome
Cytoplasm
Nucleus
   Coding sequence diversityPolymorphism
   DomainRepeat
   LigandDNA-binding
   Molecular functionActivator
Acyltransferase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage checkpoint

Inferred from mutant phenotype Ref.13. Source: UniProtKB

cellular response to ionizing radiation

Inferred from direct assay Ref.13. Source: UniProtKB

chromatin organization

Traceable author statement. Source: Reactome

circadian regulation of gene expression

Inferred from direct assay Ref.20. Source: UniProtKB

circadian rhythm

Traceable author statement Ref.1. Source: ProtInc

histone acetylation

Inferred from mutant phenotype Ref.12. Source: GOC

negative regulation of glucocorticoid receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

photoperiodism

Traceable author statement Ref.1. Source: ProtInc

positive regulation of NF-kappaB transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from genetic interaction PubMed 9576906. Source: MGI

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.17. Source: UniProtKB

proteasome-mediated ubiquitin-dependent protein catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of hair cycle

Inferred from mutant phenotype Ref.20. Source: UniProtKB

regulation of insulin secretion

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription from RNA polymerase II promoter

Traceable author statement Ref.1. Source: ProtInc

regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of type B pancreatic cell development

Inferred from sequence or structural similarity. Source: UniProtKB

response to redox state

Inferred from direct assay Ref.7. Source: UniProtKB

signal transduction

Traceable author statement Ref.1. Source: ProtInc

spermatogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: GOC

   Cellular_componentchromatoid body

Inferred from sequence or structural similarity. Source: UniProtKB

chromosome

Inferred from direct assay Ref.13. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

intracellular membrane-bounded organelle

Inferred from direct assay. Source: HPA

nucleus

Inferred from direct assay Ref.8. Source: UniProtKB

transcription factor complex

Inferred from physical interaction PubMed 9576906. Source: MGI

   Molecular_functionDNA binding

Inferred from direct assay Ref.7. Source: UniProtKB

E-box binding

Inferred from direct assay Ref.17. Source: UniProtKB

RNA polymerase II core promoter proximal region sequence-specific DNA binding

Inferred from direct assay PubMed 18411297. Source: BHF-UCL

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: BHF-UCL

RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription

Inferred from sequence or structural similarity. Source: BHF-UCL

chromatin DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

histone acetyltransferase activity

Inferred from mutant phenotype Ref.12. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.8Ref.12. Source: UniProtKB

sequence-specific DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

signal transducer activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 846846Circadian locomoter output cycles protein kaput
PRO_0000127163

Regions

Domain34 – 8451bHLH
Domain107 – 17771PAS 1
Domain262 – 33271PAS 2
Domain336 – 37944PAC
Region371 – 845475Interaction with NR3C1 By similarity
Region514 – 56451Implicated in the circadian rhythmicity By similarity
Motif32 – 4716Nuclear localization signal By similarity
Compositional bias744 – 76017Gln-rich
Compositional bias819 – 82810Poly-Gln

Amino acid modifications

Modified residue381Phosphoserine By similarity
Modified residue421Phosphoserine By similarity
Modified residue4081Phosphoserine By similarity
Modified residue4271Phosphoserine; by GSK3-beta By similarity
Modified residue4511Phosphothreonine; by CDK5 Ref.16
Modified residue4611Phosphothreonine; by CDK5 Ref.16
Cross-link67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)
Cross-link842Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity

Natural variations

Natural variant2081S → C.
Corresponds to variant rs34897046 [ dbSNP | Ensembl ].
VAR_040061
Natural variant3801E → K.
Corresponds to variant rs1056478 [ dbSNP | Ensembl ].
VAR_040062
Natural variant3951L → I.
Corresponds to variant rs6855837 [ dbSNP | Ensembl ].
VAR_029076
Natural variant5421H → R.
Corresponds to variant rs3762836 [ dbSNP | Ensembl ].
VAR_029077

Experimental info

Mutagenesis1161E → 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. Ref.9
Mutagenesis3321G → 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. Ref.9
Mutagenesis3601H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity. Ref.9
Mutagenesis3671E → 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. Ref.9
Mutagenesis4511T → F: Significant loss in phosphorylation. Ref.16
Mutagenesis4611T → F: Significant loss in phosphorylation. Ref.16
Mutagenesis6011V → 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. Ref.9
Mutagenesis8401P → 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. Ref.9
Sequence conflict4401S → P in AAF13733. Ref.1

Secondary structure

....... 846
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
O15516 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: C292B451A33E4CBF

FASTA84695,304
        10         20         30         40         50         60 
MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 

        70         80         90        100        110        120 
LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG 

       130        140        150        160        170        180 
FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL 

       190        200        210        220        230        240 
TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT 

       250        260        270        280        290        300 
HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 

       310        320        330        340        350        360 
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH 

       370        380        390        400        410        420 
QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA 

       430        440        450        460        470        480 
LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF 

       490        500        510        520        530        540 
SSQSINSQSV GSSLTQPVMS QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN 

       550        560        570        580        590        600 
IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 

       610        620        630        640        650        660 
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP SQTQSTLTAP 

       670        680        690        700        710        720 
LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ IRFSQGQQLV TKLVTAPVAC 

       730        740        750        760        770        780 
GAVMVPSTML MGQVVTAYPT FATQQQQSQT LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ 

       790        800        810        820        830        840 
PPQQFLQTSR LLHGNPSTQL ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP 


SKVQPQ 

« Hide

References

« Hide 'large scale' references
[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. expand/collapse author list , 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]"Feedback repression is required for mammalian circadian clock function."
Sato T.K., Yamada R.G., Ukai H., Baggs J.E., Miraglia L.J., Kobayashi T.J., Welsh D.K., Kay S.A., Ueda H.R., Hogenesch J.B.
Nat. Genet. 38:312-319(2006) [PubMed] [Europe PMC] [Abstract]
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]"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.
[12]"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.
[13]"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.
[14]"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.
[15]"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.
[16]"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.
[17]"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.
[18]"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.
[19]"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.
[20]"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.
[21]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS3500.1.
RefSeqNP_001254772.1. NM_001267843.1.
NP_004889.1. NM_004898.3.
XP_005265844.1. XM_005265787.1.
XP_006714117.1. XM_006714054.1.
UniGeneHs.436975.
Hs.689578.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4H10X-ray2.40B29-89[»]
ProteinModelPortalO15516.
SMRO15516. Positions 31-444.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114944. 16 interactions.
IntActO15516. 3 interactions.
STRING9606.ENSP00000308741.

PTM databases

PhosphoSiteO15516.

Proteomic databases

MaxQBO15516.
PaxDbO15516.
PRIDEO15516.

Protocols and materials databases

DNASU9575.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000309964; ENSP00000308741; ENSG00000134852.
ENST00000381322; ENSP00000370723; ENSG00000134852.
ENST00000513440; ENSP00000426983; ENSG00000134852.
GeneID9575.
KEGGhsa:9575.
UCSCuc003haz.2. human.

Organism-specific databases

CTD9575.
GeneCardsGC04M056294.
HGNCHGNC:2082. CLOCK.
HPAHPA001867.
HPA027565.
MIM601851. gene.
neXtProtNX_O15516.
PharmGKBPA26609.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG300360.
HOGENOMHOG000234382.
HOVERGENHBG050997.
InParanoidO15516.
KOK02223.
OMATPINMQG.
OrthoDBEOG71G9T7.
PhylomeDBO15516.
TreeFamTF324568.

Enzyme and pathway databases

ReactomeREACT_172623. Chromatin organization.
REACT_24941. Circadian Clock.

Gene expression databases

ArrayExpressO15516.
BgeeO15516.
CleanExHS_CLOCK.
GenevestigatorO15516.

Family and domain databases

Gene3D4.10.280.10. 1 hit.
InterProIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSPR00785. NCTRNSLOCATR.
SMARTSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
PROSITEPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiCLOCK.
GenomeRNAi9575.
NextBio35907.
PROO15516.
SOURCESearch...

Entry information

Entry nameCLOCK_HUMAN
AccessionPrimary (citable) accession number: O15516
Secondary accession number(s): A0AV01 expand/collapse secondary AC list , A2I2N9, O14516, Q9UIT8
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 1, 1998
Last modified: July 9, 2014
This is version 147 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM