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Reviewed, UniProtKB/Swiss-Prot O08785 (CLOCK_MOUSE)

Last modified October 13, 2009. Version 96. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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)
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMus

Protein attributes

Sequence length855 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

ARNTL/2-CLOCK heterodimers activate E-box element (3'-CACGTG-5') 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. Ref.8

Catalytic activity

Acetyl-CoA + histone = CoA + acetylhistone.

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

Cytoplasm. Nucleus. Note: 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 basic helix-loop-helix (bHLH) domain.

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

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

Binary interactions

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

Domain48 – 8538Helix-loop-helix motif
Domain107 – 17771PAS 1
Domain262 – 33271PAS 2
Domain336 – 37944PAC
DNA binding35 – 4713Basic motif
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

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

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.

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: 9160756] [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: 9160755] [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: 11116088] [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: 9616112] [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: 11779462] [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: 12897057] [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: 16678094] [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: 18075593] [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: 17242355] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-408, MASS SPECTROMETRY.
Tissue: Liver.
+Additional computationally mapped references.

Cross-references

Sequence databases

AF000998 mRNA. Translation: AAC53200.1.
AF146793 Genomic DNA. Translation: AAD30565.1.
IPIIPI00230536.
IPI00420596.
RefSeqNP_031741.1.
UniGeneMm.3552
Mm.392894

3D structure databases

ModBaseSearch...

Protein-protein interaction databases

IntActO08785. 8 interactions.
STRINGO08785.

PTM databases

PhosphoSiteO08785.

Proteomic databases

PRIDEO08785.

Genome annotation databases

EnsemblENSMUST00000031148; ENSMUSP00000031148; ENSMUSG00000029238; Mus musculus. [Genome view]
ENSMUST00000075159; ENSMUSP00000074656; ENSMUSG00000029238; Mus musculus. [Genome view]
ENSMUST00000113497; ENSMUSP00000109125; ENSMUSG00000029238; Mus musculus. [Genome view]
ENSMUST00000113499; ENSMUSP00000109127; ENSMUSG00000029238; Mus musculus. [Genome view]
GeneID12753.
KEGGmmu:12753.
UCSCuc008xuq.1. mouse.

Organism-specific databases

CTD12753.
MGIMGI:99698. Clock.

Phylogenomic databases

HOVERGENO08785.

Enzyme and pathway databases

BRENDA2.3.1.48. 244.

Gene expression databases

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

Family and domain databases

InterProIPR001092. HLH_basic.
IPR011598. HLH_DNA_bd.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
Gene3DG3DSA:4.10.280.10. HLH_DNA_bd. 1 hit.
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]
PROSITEPS50888. HLH. 1 hit.
PS50113. PAC. False negative.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other Resources

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: October 13, 2009
This is version 96 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

MGD cross-references

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

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents