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Q91YB0

- CLOCK_NANGA

UniProt

Q91YB0 - CLOCK_NANGA

Protein

Circadian locomoter output cycles protein kaput

Gene

Clock

Organism
Nannospalax galili (Northern Israeli blind subterranean mole rat) (Spalax galili)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 85 (01 Oct 2014)
      Sequence version 1 (01 Dec 2001)
      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 By similarity.By similarity

    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.By similarity

    GO - Molecular functioni

    1. core promoter binding Source: UniProtKB
    2. DNA binding Source: UniProtKB
    3. E-box binding Source: UniProtKB
    4. histone acetyltransferase activity Source: UniProtKB
    5. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    6. signal transducer activity Source: InterPro

    GO - Biological processi

    1. cellular response to DNA damage stimulus Source: UniProtKB-KW
    2. circadian regulation of gene expression Source: UniProtKB
    3. histone acetylation Source: GOC
    4. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    5. positive regulation of transcription, DNA-templated Source: UniProtKB
    6. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
    7. regulation of hair cycle Source: UniProtKB
    8. regulation of insulin secretion Source: UniProtKB
    9. regulation of transcription, DNA-templated Source: UniProtKB
    10. regulation of type B pancreatic cell development Source: UniProtKB
    11. response to redox state Source: UniProtKB
    12. spermatogenesis Source: UniProtKB
    13. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Activator, Transferase

    Keywords - Biological processi

    Biological rhythms, DNA damage, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Circadian locomoter output cycles protein kaput (EC:2.3.1.48)
    Gene namesi
    Name:Clock
    OrganismiNannospalax galili (Northern Israeli blind subterranean mole rat) (Spalax galili)
    Taxonomic identifieri1026970 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaSpalacidaeSpalacinaeNannospalax

    Subcellular locationi

    Cytoplasm By similarity. Nucleus PROSITE-ProRule annotation. Chromosome By similarity
    Note: Localizes to sites of DNA damage in a H2AX-independent manner. 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.By similarity

    GO - Cellular componenti

    1. chromatoid body Source: UniProtKB
    2. chromosome Source: UniProtKB-SubCell
    3. nucleus Source: UniProtKB-SubCell
    4. transcription factor complex Source: UniProtKB

    Keywords - Cellular componenti

    Chromosome, Cytoplasm, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 865865Circadian locomoter output cycles protein kaputPRO_0000262640Add
    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)By similarity
    Modified residuei408 – 4081PhosphoserineBy similarity
    Modified residuei427 – 4271Phosphoserine; by GSK3-betaBy similarity
    Modified residuei451 – 4511Phosphothreonine; by CDK5By similarity
    Modified residuei461 – 4611Phosphothreonine; by CDK5By similarity
    Cross-linki861 – 861Glycyl 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 By similarity.By similarity
    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 By similarity.By similarity

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Expressioni

    Tissue specificityi

    Expressed in brain, retina and harderian gland as well as in peripheral tissues, kidney and liver. Localizes in the brain to the suprachiasmatic nucleus (SCN).1 Publication

    Inductioni

    Exhibits no circadian rhythm expression.1 Publication

    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. 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. Interacts with KAT2B, CREBBP and EP300. Interacts with ID1, ID2 and ID3. Interacts with MTA1 By similarity.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliQ91YB0.
    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 – 864494Interaction 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 biasi483 – 847365Gln-richAdd
    BLAST

    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

    HOVERGENiHBG050997.

    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.

    Q91YB0-1 [UniParc]FASTAAdd to Basket

    « Hide

    MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF    50
    NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW 100
    KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV 150
    DQSVFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG 200
    TVDPKEPSTY EYVRFIGNFK SLNSVPTSAH NGFEGTIQRT HRPSYEDRVC 250
    FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 300
    PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW 350
    LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPDAAA 400
    DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS 450
    TPTKIPTDTS TPPRQHLPAH EKMAQRRSSF SSQSMNSQSV GPSLTQPVMS 500
    QAANLPVPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK 550
    IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLTPINMQGQ 600
    VVPTNQIQSG MNAGHIGTSQ HLIQQQSLQS TSTQQSQQSV MSGHSQQTSL 650
    ASQTQSTLTA PLYNTMVISQ PAPGSMVQIP SSMPQNSTQS ATVTTFTQDR 700
    QIRFSQGQQL VTKLVTAPVA CGAVMVPSTM LMGQVVTAYP TFATQQQQAQ 750
    TLSVTQQQPQ QQQPQQQQPQ QQQPQQQQQS SQEQQLPSVP QPSQAQLTQS 800
    PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QSQQQQQLSR 850
    HRTDSLTDPS KVQPQ 865
    Length:865
    Mass (Da):97,437
    Last modified:December 1, 2001 - v1
    Checksum:iE5003191B7578C21
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AJ318057 mRNA. Translation: CAC85403.1.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AJ318057 mRNA. Translation: CAC85403.1 .

    3D structure databases

    ProteinModelPortali Q91YB0.
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Phylogenomic databases

    HOVERGENi HBG050997.

    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. "Biological clock in total darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat."
      Avivi A., Albrecht U., Oster H., Joel A., Beiles A., Nevo E.
      Proc. Natl. Acad. Sci. U.S.A. 98:13751-13756(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH ARNTL/BMAL1, INDUCTION, TISSUE SPECIFICITY, FUNCTION.
      Tissue: Brain.

    Entry informationi

    Entry nameiCLOCK_NANGA
    AccessioniPrimary (citable) accession number: Q91YB0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 28, 2006
    Last sequence update: December 1, 2001
    Last modified: October 1, 2014
    This is version 85 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3