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Protein

Circadian locomoter output cycles protein kaput

Gene

CLOCK

Organism
Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

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 NR1D1/2 and RORA/B/G, 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, KLF10 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

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

GO - Biological processi

Complete GO annotation...

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
OrganismiPongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii)
Taxonomic identifieri9601 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaePongo
ProteomesiUP000001595 Componenti: Unplaced

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus PROSITE-ProRule annotation

  • 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

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 846846Circadian locomoter output cycles protein kaputPRO_0000262637Add
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 SUMO)By similarity
Modified residuei408 – 4081PhosphoserineBy similarity
Modified residuei427 – 4271Phosphoserine; by GSK3-betaBy similarity
Modified residuei431 – 4311PhosphoserineBy similarity
Modified residuei451 – 4511Phosphothreonine; by CDK5By similarity
Modified residuei461 – 4611Phosphothreonine; by CDK5By similarity
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
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 (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

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

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 NR3C1 in a ligand-dependent fashion. Interacts with ESR1 and estrogen stimulates this interaction. Interacts with the complex p35/CDK5. Interacts with KAT2B, CREBBP, EP300, ID1, ID2, ID3, MTA1, CIPC, RELA/p65, EIF4E, PIWIL1, DDX4, MGEA5, SIRT1 and EZH2. Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a 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. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A. Interacts with KMT2A in a circadian manner. Interacts with MYBBP1A. Interacts with THRAP3. Interacts with MED1; this interaction requires the presence of THRAP3. Interacts with NCOA2.By similarity

Structurei

3D structure databases

ProteinModelPortaliQ5RAK8.
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
Regioni450 – 570121Interaction with SIRT1By 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 – 828346Gln-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.
InParanoidiQ5RAK8.
KOiK02223.

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.

Q5RAK8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF
60 70 80 90 100
NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW
110 120 130 140 150
KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV
160 170 180 190 200
DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG
210 220 230 240 250
TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT HRPSYEDRVC
260 270 280 290 300
FVATVRLATP QFIKEMCTVE EPNEEFASRH SLEWKFLFLD HRAPPIIGYL
310 320 330 340 350
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW
360 370 380 390 400
LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELS IEESLPEIAA
410 420 430 440 450
DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS
460 470 480 490 500
TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS
510 520 530 540 550
QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK
560 570 580 590 600
IQEQLQMVHG QGLQMFLQQP NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ
610 620 630 640 650
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP
660 670 680 690 700
SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ
710 720 730 740 750
IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT
760 770 780 790 800
LSVTQQRQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL
810 820 830 840
ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ
Length:846
Mass (Da):95,354
Last modified:December 21, 2004 - v1
Checksum:iF7119E879F2C41E2
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
CR859007 mRNA. Translation: CAH91202.1.
RefSeqiNP_001125706.1. NM_001132234.1.
UniGeneiPab.7567.

Genome annotation databases

GeneIDi100172630.
KEGGipon:100172630.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
CR859007 mRNA. Translation: CAH91202.1.
RefSeqiNP_001125706.1. NM_001132234.1.
UniGeneiPab.7567.

3D structure databases

ProteinModelPortaliQ5RAK8.
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100172630.
KEGGipon:100172630.

Organism-specific databases

CTDi9575.

Phylogenomic databases

HOVERGENiHBG050997.
InParanoidiQ5RAK8.
KOiK02223.

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]
ProtoNetiSearch...

Publicationsi

  1. The German cDNA consortium
    Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Kidney.

Entry informationi

Entry nameiCLOCK_PONAB
AccessioniPrimary (citable) accession number: Q5RAK8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: December 21, 2004
Last modified: March 4, 2015
This is version 84 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.