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O08785 (CLOCK_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 133. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Circadian locomoter output cycles protein kaput
Short name=mCLOCK
EC=2.3.1.48
Gene names
Name:Clock
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length855 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. Acetylates primarily histones H3 and H4. Acetylates also a non-histone substrate: its own partner, ARNTL. Plays a role in DNA damage response (DDR) signaling during the S phase. Ref.8 Ref.10

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.

Subcellular location

Nucleus. Chromosome. Cytoplasm. Note: Localizes to sites of DNA damage in a H2AX-independent manner By similarity. Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL-dependent. Phosphorylated form located in the nucleus predominantly between C12 and C21. Nonphosphorylated form found only in the cytoplasm. Ref.5 Ref.6

Tissue specificity

Expressed equally in brain, eye, testes, ovaries, liver, heart, lung, kidney. In the brain, expression is abundant in the suprachiasmatic nuclei (SCN), in the pyriform cortex, and in the hippocampus. Low expression throughout the rest of the brain. Expression does not appear to undergo circadian oscillations. Ref.2

Induction

In the SCN, nuclear expression is lowest between CT7 and CT13. Cytoplasmic expression is highest at these times. In liver, peak levels from CT21 to CT3. Expression of both phosphorylated and unphosphorylated forms of ARNTL with other circadian clock proteins occurs between CT15 and CT18. Ref.5 Ref.6

Domain

Contains a Gln-rich C-terminal domain which could correspond to the transactivation domain.

Post-translational modification

Phosphorylation is dependent on CLOCK-ARNTL heterodimer formation.

Polymorphism

The naturally-occurring CLOCK variant, missing exon 19 (deletion of AA 514-564) due to an A-->T nucleotide transversion in a splice donor site, forms a heterodimer with DNA, but fails to activate transcription. Homozygous CLOCK mutants have a circadian rhythm that is increased from 3 to 4 hours and usually the circadian rhythmicity is lost at constant darkness. Expression of CLOCK is also reduced. There also exists an alternative spliced CLOCK variant missing both exon 18 and exon 19 (AA 484-564).

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.

Ontologies

Keywords
   Biological processBiological rhythms
DNA damage
Transcription
Transcription regulation
   Cellular componentChromosome
Cytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   DomainRepeat
   LigandDNA-binding
   Molecular functionActivator
Acyltransferase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage checkpoint

Inferred from electronic annotation. Source: Compara

cellular response to ionizing radiation

Inferred from electronic annotation. Source: Compara

circadian regulation of gene expression

Inferred from mutant phenotype Ref.10. Source: UniProtKB

histone acetylation

Inferred from electronic annotation. Source: GOC

   Cellular_componentchromosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytosol

Traceable author statement. Source: Reactome

transcription factor complex

Inferred from direct assay Ref.10. Source: UniProtKB

   Molecular_functionE-box binding

Inferred from electronic annotation. Source: Compara

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

Inferred from electronic annotation. Source: Compara

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription

Inferred by curator PubMed 14672706. Source: BHF-UCL

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

Inferred from direct assay PubMed 15560782. Source: BHF-UCL

histone acetyltransferase activity

Inferred from electronic annotation. Source: EC

signal transducer activity

Inferred from electronic annotation. Source: InterPro

transcription factor binding

Inferred from sequence alignment PubMed 11707566. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ArntlQ9WTL820EBI-79859,EBI-644534
Cry1P977847EBI-79859,EBI-1266607
Csnk1eQ9JMK22EBI-79859,EBI-771709
CSNK2BP678702EBI-79859,EBI-348169From a different organism.
NR1D2Q149952EBI-79859,EBI-6144053From a different organism.
Per2O5494310EBI-79859,EBI-1266779
PPP1CAP621362EBI-79859,EBI-357253From a different organism.
PPP1CBP621402EBI-79859,EBI-352350From a different organism.
PPP1CCP368732EBI-79859,EBI-356283From a different organism.
PPP2R1BP301542EBI-79859,EBI-357094From a different organism.
PPP2R5DQ147382EBI-79859,EBI-396563From a different organism.
RORBQ927532EBI-79859,EBI-6144615From a different organism.
RORCP514492EBI-79859,EBI-3908771From a different organism.
Sirt1Q923E411EBI-79859,EBI-1802585

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform Long (identifier: O08785-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform Short (identifier: O08785-2)

The sequence of this isoform differs from the canonical sequence as follows:
     484-513: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 855855Circadian locomoter output cycles protein kaput
PRO_0000127164

Regions

Domain34 – 8451bHLH
Domain107 – 17771PAS 1
Domain262 – 33271PAS 2
Domain336 – 37944PAC
Region514 – 56451Implicated in the circadian rhythmicity
Compositional bias484 – 855372Gln-rich
Compositional bias740 – 7456Poly-Gln
Compositional bias751 – 7599Poly-Gln
Compositional bias762 – 7698Poly-Gln
Compositional bias828 – 83710Poly-Gln

Amino acid modifications

Modified residue4081Phosphoserine Ref.9

Natural variations

Alternative sequence484 – 51330Missing in isoform Short.
VSP_002103

Experimental info

Mutagenesis571L → E: Reduced ARNTL binding. Abolishes transcriptional activation by the CLOCK-ARNTL heterodimer. Abolishes regulation of circadian clock. Ref.10
Mutagenesis741L → E: Reduced ARNTL binding. Abolishes transcriptional activation by the CLOCK-ARNTL heterodimer. Ref.10
Mutagenesis2841W → A: Reduced ARNTL binding. Slightly reduced transcriptional activation by the CLOCK-ARNTL heterodimer. Ref.10
Mutagenesis6561P → A: Reduces histone acetyltransferase activity; when associated with A-658 and A-659. Ref.7
Mutagenesis6581Y → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-659. Ref.7
Mutagenesis6591N → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-658. Ref.7
Mutagenesis6691G → A: Reduces histone acetyltransferase activity; when associated with A-670 and A-672. Ref.7
Mutagenesis6701S → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-672. Ref.7
Mutagenesis6721V → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-670. Ref.7

Secondary structure

1 ................................................................ 855
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform Long [UniParc].

Last modified July 1, 1997. Version 1.
Checksum: 9864D947049742F4

FASTA85596,393
        10         20         30         40         50         60 
MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 

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

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

       190        200        210        220        230        240 
TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLTSVSTSTH 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 EKMTQRRSSF 

       490        500        510        520        530        540 
SSQSINSQSV GPSLTQPAMS QAANLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN 

       550        560        570        580        590        600 
IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSNIQQ LTPVNMQGQV 

       610        620        630        640        650        660 
VPANQVQSGH ISTGQHMIQQ QTLQSTSTQQ SQQSVMSGHS QQTSLPSQTP STLTAPLYNT 

       670        680        690        700        710        720 
MVISQPAAGS MVQIPSSMPQ NSTQSATVTT FTQDRQIRFS QGQQLVTKLV TAPVACGAVM 

       730        740        750        760        770        780 
VPSTMLMGQV VTAYPTFATQ QQQAQTLSVT QQQQQQQQQP PQQQQQQQQS SQEQQLPSVQ 

       790        800        810        820        830        840 
QPAQAQLGQP PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QPQQQQQLPR 

       850 
HRTDSLTDPS KVQPQ

« Hide

Isoform Short [UniParc].

Checksum: FABAE927F765B680
Show »

FASTA82593,371

References

« Hide 'large scale' references
[1]"Functional identification of the mouse circadian clock gene by transgenic BAC rescue."
Antoch M.P., Song E.J., Chang A.M., Vitaterna M.H., Zhao Y., Wilsbacher L.D., Sangoram A.M., King D.P., Pinto L.H., Takahashi J.S.
Cell 89:655-667(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
Strain: 129.
[2]"Positional cloning of the mouse circadian clock gene."
King D.P., Zhao Y., Sangoram A.M., Wilsbacher L.D., Tanaka M., Antoch M.P., Steeves T.D.L., Vitaterna M.H., Kornhauser J.M., Lowrey P.L., Turek F.W., Takahashi J.S.
Cell 89:641-653(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS LONG AND SHORT), TISSUE SPECIFICITY, IDENTIFICATION OF CLOCK VARIANT.
Strain: C57BL/6 X BALB/c.
Tissue: Suprachiasmatic nucleus.
[3]"The mouse Clock locus: sequence and comparative analysis of 204 kb from mouse chromosome 5."
Wilsbacher L.D., Sangoram A.M., Antoch M.P., Takahashi J.S.
Genome Res. 10:1928-1940(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Strain: 129/Sv.
[4]"Role of the CLOCK protein in the mammalian circadian mechanism."
Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D., King D.P., Takahashi J.S., Weitz C.J.
Science 280:1564-1569(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARNTL.
[5]"Posttranslational mechanisms regulate the mammalian circadian clock."
Lee C., Etchegaray J.-P., Cagampang F.R.A., Loudon A.S.I., Reppert S.M.
Cell 107:855-867(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARNTL; PER1; PER2; CRY1; CRY2 AND CSNK1E, PHOSPHORYLATION, SUBCELLULAR LOCATION, INDUCTION.
[6]"BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system."
Kondratov R.V., Chernov M.V., Kondratova A.A., Gorbacheva V.Y., Gudkov A.V., Antoch M.P.
Genes Dev. 17:1921-1932(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARNTL, PHOSPHORYLATION, SUBCELLULAR LOCATION, INDUCTION.
[7]"Circadian regulator CLOCK is a histone acetyltransferase."
Doi M., Hirayama J., Sassone-Corsi P.
Cell 125:497-508(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: HISTONE ACETYLTRANSFERASE ACTIVITY, MUTAGENESIS OF PRO-656; TYR-658; ASN-659; GLY-669; SER-670 AND VAL-672.
[8]"CLOCK-mediated acetylation of BMAL1 controls circadian function."
Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K., Nakahata Y., Sassone-Corsi P.
Nature 450:1086-1090(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACETYLATION OF ARNTL.
[9]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-408, MASS SPECTROMETRY.
Tissue: Liver.
[10]"Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex."
Huang N., Chelliah Y., Shan Y., Taylor C.A., Yoo S.H., Partch C., Green C.B., Zhang H., Takahashi J.S.
Science 337:189-194(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 26-384 IN COMPLEX WITH ARNTL, FUNCTION, INTERACTION WITH ARNTL, MUTAGENESIS OF LEU-57; LEU-74 AND TRP-284.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		AF000998 mRNA. Translation: AAC53200.1.
AF146793 Genomic DNA. Translation: AAD30565.1.
IPIIPI00230536.
IPI00420596.
RefSeqNP_031741.1. NM_007715.5.
UniGeneMm.3552.
Mm.392894.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4F3LX-ray2.27A26-384[»]
ProteinModelPortalO08785.
SMRO08785. Positions 31-444.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-30958N.
IntActO08785. 26 interactions.
MINTMINT-4654078.

PTM databases

PhosphoSiteO08785.

Proteomic databases

PaxDbO08785.
PRIDEO08785.

Protocols and materials databases

DNASU12753.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000075159; ENSMUSP00000074656; ENSMUSG00000029238.
GeneID12753.
KEGGmmu:12753.

Organism-specific databases

CTD9575.
MGIMGI:99698. Clock.

Phylogenomic databases

eggNOGNOG300360.
GeneTreeENSGT00650000092935.
HOGENOMHOG000234382.
HOVERGENHBG050997.
InParanoidO08785.
KOK02223.
OMAAHEKMAQ.
OrthoDBEOG476JZV.

Enzyme and pathway databases

ReactomeREACT_109335. Circadian Clock.
REACT_24972. Circadian Clock (mouse).

Gene expression databases

ArrayExpressO08785.
BgeeO08785.
CleanExMM_CLOCK.
GenevestigatorO08785.
GermOnlineENSMUSG00000029238. Mus musculus.

Family and domain databases

Gene3D4.10.280.10. 1 hit.
InterProIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
PfamPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
PRINTSPR00785. NCTRNSLOCATR.
SMARTSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMSSF47459. HLH_basic. 1 hit.
PROSITEPS50888. BHLH. 1 hit.
PS50113. PAC. False negative.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio282092.
SOURCESearch...

Entry information

Entry nameCLOCK_MOUSE
AccessionPrimary (citable) accession number: O08785
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 1, 1997
Last modified: May 1, 2013
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents