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O15516

- CLOCK_HUMAN

UniProt

O15516 - CLOCK_HUMAN

Protein

Circadian locomoter output cycles protein kaput

Gene

CLOCK

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 149 (01 Oct 2014)
      Sequence version 1 (01 Jan 1998)
      Previous versions | rss
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    Functioni

    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, ATF4, MTA1 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/DEC1.7 Publications

    Catalytic activityi

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

    Enzyme regulationi

    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.

    GO - Molecular functioni

    1. chromatin DNA binding Source: UniProtKB
    2. core promoter binding Source: UniProtKB
    3. DNA binding Source: UniProtKB
    4. E-box binding Source: UniProtKB
    5. histone acetyltransferase activity Source: UniProtKB
    6. protein binding Source: UniProtKB
    7. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: BHF-UCL
    8. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    9. RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription Source: BHF-UCL
    10. sequence-specific DNA binding Source: UniProtKB
    11. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    12. signal transducer activity Source: InterPro

    GO - Biological processi

    1. cellular response to ionizing radiation Source: UniProtKB
    2. chromatin organization Source: Reactome
    3. circadian regulation of gene expression Source: UniProtKB
    4. circadian rhythm Source: ProtInc
    5. DNA damage checkpoint Source: UniProtKB
    6. histone acetylation Source: GOC
    7. negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
    8. negative regulation of transcription, DNA-templated Source: UniProtKB
    9. photoperiodism Source: ProtInc
    10. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    11. positive regulation of transcription, DNA-templated Source: UniProtKB
    12. positive regulation of transcription from RNA polymerase II promoter Source: MGI
    13. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
    14. regulation of hair cycle Source: UniProtKB
    15. regulation of insulin secretion Source: UniProtKB
    16. regulation of transcription, DNA-templated Source: UniProtKB
    17. regulation of transcription from RNA polymerase II promoter Source: ProtInc
    18. regulation of type B pancreatic cell development Source: UniProtKB
    19. response to redox state Source: UniProtKB
    20. signal transduction Source: ProtInc
    21. spermatogenesis Source: UniProtKB
    22. transcription from RNA polymerase II promoter Source: GOC

    Keywords - Molecular functioni

    Activator, Acyltransferase, Transferase

    Keywords - Biological processi

    Biological rhythms, DNA damage, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_172610. HATs acetylate histones.
    REACT_24941. Circadian Clock.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Circadian locomoter output cycles protein kaput (EC:2.3.1.48)
    Short name:
    hCLOCK
    Alternative name(s):
    Class E basic helix-loop-helix protein 8
    Short name:
    bHLHe8
    Gene namesi
    Name:CLOCK
    Synonyms:BHLHE8, KIAA0334
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 4

    Organism-specific databases

    HGNCiHGNC:2082. CLOCK.

    Subcellular locationi

    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. Sequestered to the cytoplasm in the presence of ID2 By similarity. Localizes to sites of DNA damage in a H2AX-independent manner.By similarity

    GO - Cellular componenti

    1. chromatoid body Source: UniProtKB
    2. chromosome Source: UniProtKB
    3. cytosol Source: Reactome
    4. intracellular membrane-bounded organelle Source: HPA
    5. nucleus Source: UniProtKB
    6. transcription factor complex Source: MGI

    Keywords - Cellular componenti

    Chromosome, Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi116 – 1161E → 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. 1 Publication
    Mutagenesisi332 – 3321G → 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. 1 Publication
    Mutagenesisi360 – 3601H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity. 1 Publication
    Mutagenesisi367 – 3671E → 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. 1 Publication
    Mutagenesisi451 – 4511T → F: Significant loss in phosphorylation. 1 Publication
    Mutagenesisi461 – 4611T → F: Significant loss in phosphorylation. 1 Publication
    Mutagenesisi601 – 6011V → 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. 1 Publication
    Mutagenesisi840 – 8401P → 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. 1 Publication

    Organism-specific databases

    PharmGKBiPA26609.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 846846Circadian locomoter output cycles protein kaputPRO_0000127163Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei38 – 381PhosphoserineBy similarity
    Modified residuei42 – 421PhosphoserineBy similarity
    Cross-linki67 – 67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)
    Modified residuei408 – 4081PhosphoserineBy similarity
    Modified residuei427 – 4271Phosphoserine; by GSK3-betaBy similarity
    Modified residuei451 – 4511Phosphothreonine; by CDK51 Publication
    Modified residuei461 – 4611Phosphothreonine; by CDK51 Publication
    Cross-linki842 – 842Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity

    Post-translational modificationi

    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.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.1 Publication
    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.1 Publication

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiO15516.
    PaxDbiO15516.
    PRIDEiO15516.

    PTM databases

    PhosphoSiteiO15516.

    Expressioni

    Tissue specificityi

    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).2 Publications

    Gene expression databases

    ArrayExpressiO15516.
    BgeeiO15516.
    CleanExiHS_CLOCK.
    GenevestigatoriO15516.

    Organism-specific databases

    HPAiHPA001867.
    HPA027565.

    Interactioni

    Subunit structurei

    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. Interacts with ID1, ID2 and ID3. Interacts with MTA1.6 Publications

    Protein-protein interaction databases

    BioGridi114944. 16 interactions.
    DIPiDIP-46009N.
    IntActiO15516. 3 interactions.
    STRINGi9606.ENSP00000308741.

    Structurei

    Secondary structure

    1
    846
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi33 – 5826
    Beta strandi61 – 633
    Helixi70 – 8920

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    4H10X-ray2.40B29-89[»]
    ProteinModelPortaliO15516.
    SMRiO15516. Positions 31-444.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini34 – 8451bHLHPROSITE-ProRule annotationAdd
    BLAST
    Domaini107 – 17771PAS 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini262 – 33271PAS 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini336 – 37944PACAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni371 – 845475Interaction with NR3C1By similarityAdd
    BLAST
    Regioni514 – 56451Implicated in the circadian rhythmicityBy similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi32 – 4716Nuclear localization signalBy similarityAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi744 – 76017Gln-richAdd
    BLAST
    Compositional biasi819 – 82810Poly-Gln

    Sequence similaritiesi

    Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
    Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiNOG300360.
    HOGENOMiHOG000234382.
    HOVERGENiHBG050997.
    InParanoidiO15516.
    KOiK02223.
    OMAiTPINMQG.
    OrthoDBiEOG71G9T7.
    PhylomeDBiO15516.
    TreeFamiTF324568.

    Family and domain databases

    Gene3Di4.10.280.10. 1 hit.
    InterProiIPR011598. bHLH_dom.
    IPR001067. Nuc_translocat.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view]
    PfamiPF00010. HLH. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view]
    PRINTSiPR00785. NCTRNSLOCATR.
    SMARTiSM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view]
    SUPFAMiSSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    PROSITEiPS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    O15516-1 [UniParc]FASTAAdd to Basket

    « Hide

    MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF    50
    NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW 100
    KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV 150
    DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG 200
    TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT HRPSYEDRVC 250
    FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 300
    PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW 350
    LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA 400
    DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS 450
    TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS 500
    QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK 550
    IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 600
    VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP 650
    SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ 700
    IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT 750
    LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL 800
    ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ 846
    Length:846
    Mass (Da):95,304
    Last modified:January 1, 1998 - v1
    Checksum:iC292B451A33E4CBF
    GO

    Sequence cautioni

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

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti440 – 4401S → P in AAF13733. (PubMed:10198158)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti208 – 2081S → C.
    Corresponds to variant rs34897046 [ dbSNP | Ensembl ].
    VAR_040061
    Natural varianti380 – 3801E → K.
    Corresponds to variant rs1056478 [ dbSNP | Ensembl ].
    VAR_040062
    Natural varianti395 – 3951L → I.
    Corresponds to variant rs6855837 [ dbSNP | Ensembl ].
    VAR_029076
    Natural varianti542 – 5421H → R.
    Corresponds to variant rs3762836 [ dbSNP | Ensembl ].
    VAR_029077

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    CCDSiCCDS3500.1.
    RefSeqiNP_001254772.1. NM_001267843.1.
    NP_004889.1. NM_004898.3.
    XP_005265844.1. XM_005265787.1.
    XP_006714117.1. XM_006714054.1.
    UniGeneiHs.436975.
    Hs.689578.

    Genome annotation databases

    EnsembliENST00000309964; ENSP00000308741; ENSG00000134852.
    ENST00000381322; ENSP00000370723; ENSG00000134852.
    ENST00000513440; ENSP00000426983; ENSG00000134852.
    GeneIDi9575.
    KEGGihsa:9575.
    UCSCiuc003haz.2. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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 .
    CCDSi CCDS3500.1.
    RefSeqi NP_001254772.1. NM_001267843.1.
    NP_004889.1. NM_004898.3.
    XP_005265844.1. XM_005265787.1.
    XP_006714117.1. XM_006714054.1.
    UniGenei Hs.436975.
    Hs.689578.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    4H10 X-ray 2.40 B 29-89 [» ]
    ProteinModelPortali O15516.
    SMRi O15516. Positions 31-444.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 114944. 16 interactions.
    DIPi DIP-46009N.
    IntActi O15516. 3 interactions.
    STRINGi 9606.ENSP00000308741.

    PTM databases

    PhosphoSitei O15516.

    Proteomic databases

    MaxQBi O15516.
    PaxDbi O15516.
    PRIDEi O15516.

    Protocols and materials databases

    DNASUi 9575.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000309964 ; ENSP00000308741 ; ENSG00000134852 .
    ENST00000381322 ; ENSP00000370723 ; ENSG00000134852 .
    ENST00000513440 ; ENSP00000426983 ; ENSG00000134852 .
    GeneIDi 9575.
    KEGGi hsa:9575.
    UCSCi uc003haz.2. human.

    Organism-specific databases

    CTDi 9575.
    GeneCardsi GC04M056294.
    HGNCi HGNC:2082. CLOCK.
    HPAi HPA001867.
    HPA027565.
    MIMi 601851. gene.
    neXtProti NX_O15516.
    PharmGKBi PA26609.
    HUGEi Search...
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG300360.
    HOGENOMi HOG000234382.
    HOVERGENi HBG050997.
    InParanoidi O15516.
    KOi K02223.
    OMAi TPINMQG.
    OrthoDBi EOG71G9T7.
    PhylomeDBi O15516.
    TreeFami TF324568.

    Enzyme and pathway databases

    Reactomei REACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_172610. HATs acetylate histones.
    REACT_24941. Circadian Clock.

    Miscellaneous databases

    GeneWikii CLOCK.
    GenomeRNAii 9575.
    NextBioi 35907.
    PROi O15516.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O15516.
    Bgeei O15516.
    CleanExi HS_CLOCK.
    Genevestigatori O15516.

    Family and domain databases

    Gene3Di 4.10.280.10. 1 hit.
    InterProi IPR011598. bHLH_dom.
    IPR001067. Nuc_translocat.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view ]
    Pfami PF00010. HLH. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view ]
    PRINTSi PR00785. NCTRNSLOCATR.
    SMARTi SM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view ]
    SUPFAMi SSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    PROSITEi PS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.
      , 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. 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. "The transcriptional repressor ID2 can interact with the canonical clock components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 expression."
      Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.
      J. Biol. Chem. 285:38987-39000(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ID2.
    12. "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.
    13. "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.
    14. "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.
    15. "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.
    16. "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.
    17. "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.
    18. "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.
    19. "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.
    20. "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.
    21. "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.
    22. "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.

    Entry informationi

    Entry nameiCLOCK_HUMAN
    AccessioniPrimary (citable) accession number: O15516
    Secondary accession number(s): A0AV01
    , A2I2N9, O14516, Q9UIT8
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1999
    Last sequence update: January 1, 1998
    Last modified: October 1, 2014
    This is version 149 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (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.

    Miscellaneousi

    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.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 4
      Human chromosome 4: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3