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O15516 (CLOCK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 143. 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

ARNTL/2-CLOCK heterodimers activate E-box element (5'-CACGTG-3') transcription of a number of proteins of the circadian clock. Activates transcription of PER1 and PER2. This transcription is inhibited in a feedback loop by PER and CRY proteins. Has intrinsic histone acetyltransferase activity and this enzymatic function contributes to chromatin-remodeling events implicated in circadian control of gene expression By similarity. Acetylates primarily histones H3 and H4 By similarity. Acetylates also a non-histone substrate: ARNTL By similarity. Plays a role in DNA damage response (DDR) signaling during the S phase. Ref.8

Catalytic activity

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

Subunit structure

Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, ARNTL or ARNTL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerization with ARNTL is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and ARNTL. Interaction with PER and CRY proteins requires translocation to the nucleus. Interaction of the CLOCK-ARNTL heterodimer with PER or CRY inhibits transcription activation. Binds weakly ARNTL and ARNTL2 to form heterodimers which bind poorly to the E-box motif. Interacts with CIPC By similarity.

Subcellular location

Nucleus. Chromosome. Cytoplasm By similarity. Nucleus By similarity. Note: Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL-dependent. Phosphorylated form located in the nucleus By similarity. Localizes to sites of DNA damage in a H2AX-independent manner. Ref.8

Tissue specificity

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

Post-translational modification

Phosphorylation is dependent on CLOCK-ARNTL heterodimer formation By similarity.

Miscellaneous

CLOCK-ARNTL double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-ARNTL 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
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage checkpoint

Inferred from mutant phenotype Ref.8. Source: UniProtKB

cellular response to ionizing radiation

Inferred from direct assay Ref.8. Source: UniProtKB

circadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

histone acetylation

Inferred from electronic annotation. Source: GOC

photoperiodism

Traceable author statement Ref.1. Source: ProtInc

signal transduction

Traceable author statement Ref.1. Source: ProtInc

   Cellular_componentchromosome

Inferred from direct assay Ref.8. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay. Source: HPA

transcription factor complex

Inferred from physical interaction PubMed 9576906. Source: MGI

   Molecular_functionE-box binding

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

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

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

histone acetyltransferase activity

Inferred from electronic annotation. Source: UniProtKB-EC

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
Region514 – 56451Implicated in the circadian rhythmicity By similarity
Compositional bias744 – 76017Gln-rich
Compositional bias819 – 82810Poly-Gln

Amino acid modifications

Modified residue4081Phosphoserine 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. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with K-367 and L-601. Ref.7
Mutagenesis3321G → E: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with L-840. Ref.7
Mutagenesis3601H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity. Ref.7
Mutagenesis3671E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition CLOCK-ARNTL transcriptional activity; when associated with E-116 and L-601. Ref.7
Mutagenesis6011V → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with K-116 and K-367. Ref.7
Mutagenesis8401P → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with E-332. Ref.7
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]"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.
[8]"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.
+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.
RefSeqNP_001254772.1. NM_001267843.1.
NP_004889.1. NM_004898.3.
XP_005265844.1. XM_005265787.1.
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

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: March 19, 2014
This is version 143 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