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O08785 (CLOCK_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 143. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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 lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length855 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. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2 and also genes implicated in glucose and lipid metabolism. Represses glucocorticoid receptor (GR)-induced transcriptional activity by reducing the association of 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. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. Ref.7 Ref.8 Ref.11 Ref.15 Ref.16 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.28 Ref.32 Ref.35 Ref.36 Ref.37 Ref.38 Ref.40

Catalytic activity

Acetyl-CoA + [histone] = CoA + acetyl-[histone]. Ref.8

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. 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. Interacts with CIPC. Interacts with the complex p35/CDK5. Interacts with NR3C1 in a ligand-dependent fashion. Interacts with ESR1 and estrogen stimulates this interaction. Interacts with RELA/p65, EIF4E, PIWIL1, DDX4, PER2 and MGEA5. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Ref.4 Ref.5 Ref.6 Ref.9 Ref.10 Ref.13 Ref.14 Ref.15 Ref.25 Ref.26 Ref.29 Ref.31 Ref.33 Ref.40

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/BMAL1-dependent. Phosphorylated form located in the nucleus predominantly between C12 and C21. Nonphosphorylated form found only in the cytoplasm. Ref.5 Ref.6 Ref.9 Ref.10 Ref.17 Ref.25

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 Ref.25

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/BMAL1 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

Ubiquitinated, leading to its proteasomal degradation. Ref.9 Ref.30

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. Ref.29 Ref.30

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: the hyperphosphorylated form peaks at midnight (CT18), while the hypophosphorylated form is abundant throughout the day. Ref.5 Ref.6 Ref.14 Ref.17 Ref.31

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. Ref.33

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
   PTMGlycoprotein
Isopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage checkpoint

Inferred from electronic annotation. Source: Ensembl

cellular response to ionizing radiation

Inferred from electronic annotation. Source: Ensembl

circadian regulation of gene expression

Inferred from mutant phenotype Ref.15Ref.19Ref.40. Source: UniProtKB

circadian rhythm

Inferred from direct assay Ref.6. Source: MGI

positive regulation of NF-kappaB transcription factor activity

Inferred from mutant phenotype Ref.26. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 14672706PubMed 15147242PubMed 15193144. Source: BHF-UCL

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.7Ref.16. Source: UniProtKB

regulation of hair cycle

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from direct assay Ref.40. Source: UniProtKB

spermatogenesis

Inferred from mutant phenotype Ref.25. Source: UniProtKB

transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 15147242. Source: GOC

   Cellular_componentchromatoid body

Inferred from direct assay Ref.25. Source: UniProtKB

chromosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoplasm

Inferred from direct assay Ref.6. Source: MGI

cytosol

Traceable author statement. Source: Reactome

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.10. Source: UniProtKB

transcription factor complex

Inferred from direct assay Ref.40. Source: UniProtKB

   Molecular_functionE-box binding

Inferred from direct assay Ref.7Ref.16Ref.19. Source: UniProtKB

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

Inferred from electronic annotation. Source: Ensembl

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

Inferred from direct assay PubMed 15147242. Source: BHF-UCL

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

core promoter binding

Inferred from direct assay Ref.38. Source: UniProtKB

histone acetyltransferase activity

Inferred from mutant phenotype Ref.15. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.40. Source: UniProtKB

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

ArntlQ9WTL824EBI-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.
PrkcaP204443EBI-79859,EBI-6976815
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
Region371 – 854484Interaction with NR3C1
Region514 – 56451Implicated in the circadian rhythmicity
Motif32 – 4716Nuclear localization signal Ref.17
Compositional bias484 – 855372Gln-rich
Compositional bias740 – 7456Poly-Gln
Compositional bias751 – 7599Poly-Gln
Compositional bias762 – 7698Poly-Gln
Compositional bias828 – 83710Poly-Gln

Amino acid modifications

Modified residue381Phosphoserine Ref.17
Modified residue421Phosphoserine Ref.17
Modified residue4081Phosphoserine Ref.12
Modified residue4271Phosphoserine; by GSK3-beta Ref.14 Ref.17
Modified residue4311Phosphoserine Ref.14
Modified residue4511Phosphothreonine; by CDK5 Ref.31
Modified residue4611Phosphothreonine; by CDK5 Ref.31
Cross-link67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) Ref.33
Cross-link851Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) Ref.33

Natural variations

Alternative sequence484 – 51330Missing in isoform Short.
VSP_002103

Experimental info

Mutagenesis381S → D: Significant decrease in transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer. Significant decrease in transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer, reduced nuclear localization and DNA-binding; when associated with D-42. Ref.17
Mutagenesis421S → D: Significant decrease in transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer. Significant decrease in transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer, reduced nuclear localization and DNA-binding; when associated with D-38. Ref.17
Mutagenesis571L → E: Reduced ARNTL/BMAL1 binding. Abolishes transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer. Abolishes regulation of circadian clock. Ref.40
Mutagenesis671K → R: Decrease in sumoylation and its transcriptional activity. Abolishes sumoylation and interaction with ESR1 and decrease in its transcriptional activity; when associated with R-851. Ref.33
Mutagenesis741L → E: Reduced ARNTL/BMAL1 binding. Abolishes transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer. Ref.40
Mutagenesis2841W → A: Reduced ARNTL/BMAL1 binding. Slightly reduced transcriptional activation by the CLOCK-ARNTL/BMAL1 heterodimer. Ref.40
Mutagenesis4271S → A: Significant loss of phosphorylation. Ref.14 Ref.17
Mutagenesis4311S → A: Significant loss of phosphorylation. Ref.14
Mutagenesis6561P → A: Reduces histone acetyltransferase activity; when associated with A-658 and A-659. Ref.8
Mutagenesis6581Y → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-659. Ref.8
Mutagenesis6591N → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-658. Ref.8
Mutagenesis6691G → A: Reduces histone acetyltransferase activity; when associated with A-670 and A-672. Ref.8
Mutagenesis6701S → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-672. Ref.8
Mutagenesis6721V → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-670. Ref.8
Mutagenesis8511K → R: Decrease in sumoylation and its transcriptional activity. Abolishes sumoylation and interaction with ESR1 and decrease in its transcriptional activity; when associated with R-67. Ref.33

Secondary structure

................................................................ 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/BMAL1.
[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/BMAL1; 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/BMAL1, PHOSPHORYLATION, SUBCELLULAR LOCATION, INDUCTION.
[7]"Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2."
Schoenhard J.A., Smith L.H., Painter C.A., Eren M., Johnson C.H., Vaughan D.E.
J. Mol. Cell. Cardiol. 35:473-481(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"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: MUTAGENESIS OF PRO-656; TYR-658; ASN-659; GLY-669; SER-670 AND VAL-672, FUNCTION, CATALYTIC ACTIVITY.
[9]"BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer."
Kwon I., Lee J., Chang S.H., Jung N.C., Lee B.J., Son G.H., Kim K., Lee K.H.
Mol. Cell. Biol. 26:7318-7330(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH ARNTL/BMAL1, UBIQUITINATION, PROTEASOMAL DEGRADATION.
[10]"CIPC is a mammalian circadian clock protein without invertebrate homologues."
Zhao W.N., Malinin N., Yang F.C., Staknis D., Gekakis N., Maier B., Reischl S., Kramer A., Weitz C.J.
Nat. Cell Biol. 9:268-275(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH CIPC.
[11]"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/BMAL1.
[12]"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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[13]"Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK."
Langmesser S., Tallone T., Bordon A., Rusconi S., Albrecht U.
BMC Mol. Biol. 9:41-41(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PER2.
[14]"A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation."
Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.
Cell Cycle 8:4138-4146(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-427 AND SER-431, MUTAGENESIS OF SER-427 AND SER-431, INTERACTION WITH GSK3B AND ARNTL/BMAL1.
[15]"Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications."
Nader N., Chrousos G.P., Kino T.
FASEB J. 23:1572-1583(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NR3C1.
[16]"Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription."
Sasaki M., Yoshitane H., Du N.H., Okano T., Fukada Y.
J. Biol. Chem. 284:25149-25159(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[17]"Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription."
Yoshitane H., Takao T., Satomi Y., Du N.H., Okano T., Fukada Y.
Mol. Cell. Biol. 29:3675-3686(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, PHOSPHORYLATION AT SER-38; SER-42 AND SER-427, MUTAGENESIS OF SER-38; SER-42 AND SER-427.
[18]"Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1."
Nakahata Y., Sahar S., Astarita G., Kaluzova M., Sassone-Corsi P.
Science 324:654-657(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[19]"CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2."
Doi R., Oishi K., Ishida N.
J. Biol. Chem. 285:22114-22121(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[20]"Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes."
Marcheva B., Ramsey K.M., Buhr E.D., Kobayashi Y., Su H., Ko C.H., Ivanova G., Omura C., Mo S., Vitaterna M.H., Lopez J.P., Philipson L.H., Bradfield C.A., Crosby S.D., Je Bailey L., Wang X., Takahashi J.S., Bass J.
Nature 466:627-631(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[21]"CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function."
Andrews J.L., Zhang X., McCarthy J.J., McDearmon E.L., Hornberger T.A., Russell B., Campbell K.S., Arbogast S., Reid M.B., Walker J.R., Hogenesch J.B., Takahashi J.S., Esser K.A.
Proc. Natl. Acad. Sci. U.S.A. 107:19090-19095(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[22]"Deficiency in core circadian protein Bmal1 is associated with a prothrombotic and vascular phenotype."
Somanath P.R., Podrez E.A., Chen J., Ma Y., Marchant K., Antoch M., Byzova T.V.
J. Cell. Physiol. 226:132-140(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[23]"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.
[24]"Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E boxes and requires the proteasome."
Stratmann M., Suter D.M., Molina N., Naef F., Schibler U.
Mol. Cell 48:277-287(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[25]"Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA processing granule of male germ cells."
Peruquetti R.L., de Mateo S., Sassone-Corsi P.
PLoS ONE 7:E42695-E42695(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH EIF4E; PIWIL1 AND DDX4.
[26]"Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated transcription."
Spengler M.L., Kuropatwinski K.K., Comas M., Gasparian A.V., Fedtsova N., Gleiberman A.S., Gitlin I.I., Artemicheva N.M., Deluca K.A., Gudkov A.V., Antoch M.P.
Proc. Natl. Acad. Sci. U.S.A. 109:E2457-E2465(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RELA/P65.
[27]"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.
[28]"The molecular clock regulates circadian transcription of tissue factor gene."
Oishi K., Koyanagi S., Ohkura N.
Biochem. Biophys. Res. Commun. 431:332-335(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[29]"Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock."
Kaasik K., Kivimae S., Allen J.J., Chalkley R.J., Huang Y., Baer K., Kissel H., Burlingame A.L., Shokat K.M., Ptacek L.J., Fu Y.H.
Cell Metab. 17:291-302(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION, INTERACTION WITH MGEA5.
[30]"O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination."
Li M.D., Ruan H.B., Hughes M.E., Lee J.S., Singh J.P., Jones S.P., Nitabach M.N., Yang X.
Cell Metab. 17:303-310(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION, UBIQUITINATION.
[31]"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, INTERACTION WITH THE COMPLEX P35/CDK5.
[32]"Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration."
Musiek E.S., Lim M.M., Yang G., Bauer A.Q., Qi L., Lee Y., Roh J.H., Ortiz-Gonzalez X., Dearborn J.T., Culver J.P., Herzog E.D., Hogenesch J.B., Wozniak D.F., Dikranian K., Giasson B.I., Weaver D.R., Holtzman D.M., Fitzgerald G.A.
J. Clin. Invest. 123:5389-5400(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[33]"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 AT LYS-67 AND LYS-851, DESUMOYLATION, INTERACTION WITH ESR1, MUTAGENESIS OF LYS-67 AND LYS-851.
[34]"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.
[35]"Clock upregulates intercellular adhesion molecule-1 expression and promotes mononuclear cells adhesion to endothelial cells."
Gao Y., Meng D., Sun N., Zhu Z., Zhao R., Lu C., Chen S., Hua L., Qian R.
Biochem. Biophys. Res. Commun. 443:586-591(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[36]"CLOCK:BMAL1 is a pioneer-like transcription factor."
Menet J.S., Pescatore S., Rosbash M.
Genes Dev. 28:8-13(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[37]"CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity via SIRT1."
Zhou B., Zhang Y., Zhang F., Xia Y., Liu J., Huang R., Wang Y., Hu Y., Wu J., Dai C., Wang H., Tu Y., Peng X., Wang Y., Zhai Q.
Hepatology 0:0-0(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[38]"Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression."
Annayev Y., Adar S., Chiou Y.Y., Lieb J., Sancar A., Ye R.
J. Biol. Chem. 289:5013-5024(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[39]"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.
[40]"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/BMAL1, FUNCTION, INTERACTION WITH ARNTL/BMAL1, 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.
RefSeqNP_031741.1. NM_007715.6.
XP_006534807.1. XM_006534744.1.
UniGeneMm.3552.
Mm.392894.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4F3LX-ray2.27A26-384[»]
DisProtDP00734.
ProteinModelPortalO08785.
SMRO08785. Positions 31-444.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198756. 16 interactions.
DIPDIP-30958N.
IntActO08785. 28 interactions.
MINTMINT-4654078.

PTM databases

PhosphoSiteO08785.

Proteomic databases

PaxDbO08785.
PRIDEO08785.

Protocols and materials databases

DNASU12753.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000075159; ENSMUSP00000074656; ENSMUSG00000029238. [O08785-1]
GeneID12753.
KEGGmmu:12753.
UCSCuc008xuq.1. mouse. [O08785-1]

Organism-specific databases

CTD9575.
MGIMGI:99698. Clock.

Phylogenomic databases

eggNOGNOG300360.
GeneTreeENSGT00650000092935.
HOGENOMHOG000234382.
HOVERGENHBG050997.
InParanoidO08785.
KOK02223.
OMATPINMQG.
OrthoDBEOG71G9T7.
PhylomeDBO08785.
TreeFamTF324568.

Enzyme and pathway databases

ReactomeREACT_109335. Circadian Clock.
REACT_24972. Circadian Clock.

Gene expression databases

ArrayExpressO08785.
BgeeO08785.
CleanExMM_CLOCK.
GenevestigatorO08785.

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

NextBio282092.
PROO08785.
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: April 16, 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

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

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