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Q5RAK8

- CLOCK_PONAB

UniProt

Q5RAK8 - CLOCK_PONAB

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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: 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, 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 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

  1. DNA binding Source: UniProtKB
  2. E-box binding Source: UniProtKB
  3. chromatin DNA binding Source: UniProtKB
  4. core promoter binding Source: UniProtKB
  5. histone acetyltransferase activity Source: UniProtKB
  6. sequence-specific DNA binding Source: UniProtKB
  7. sequence-specific DNA binding transcription factor activity Source: UniProtKB
  8. 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. negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
  5. negative regulation of transcription, DNA-templated Source: UniProtKB
  6. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  7. positive regulation of transcription, DNA-templated Source: UniProtKB
  8. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  9. regulation of hair cycle Source: UniProtKB
  10. regulation of insulin secretion Source: UniProtKB
  11. regulation of transcription, DNA-templated Source: UniProtKB
  12. regulation of type B pancreatic cell development Source: UniProtKB
  13. response to redox state Source: UniProtKB
  14. spermatogenesis Source: UniProtKB
  15. transcription, DNA-templated Source: UniProtKB-KW
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: Unplaced

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity. 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.

GO - Cellular componenti

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

Keywords - Cellular componenti

Chromosome, Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 846846Circadian locomoter output cycles protein kaput
PRO_0000262637Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei38 – 381Phosphoserine By similarity
Modified residuei42 – 421Phosphoserine By similarity
Cross-linki67 – 67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Modified residuei408 – 4081Phosphoserine By similarity
Modified residuei427 – 4271Phosphoserine; by GSK3-beta By similarity
Modified residuei451 – 4511Phosphothreonine; by CDK5 By similarity
Modified residuei461 – 4611Phosphothreonine; by CDK5 By 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.
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 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 By similarity.

Structurei

3D structure databases

ProteinModelPortaliQ5RAK8.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini34 – 8451bHLH
Add
BLAST
Domaini107 – 17771PAS 1
Add
BLAST
Domaini262 – 33271PAS 2
Add
BLAST
Domaini336 – 37944PAC
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni371 – 845475Interaction with NR3C1 By similarity
Add
BLAST
Regioni514 – 56451Implicated in the circadian rhythmicity By similarity
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi32 – 4716Nuclear localization signal By similarity
Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi483 – 828346Gln-rich
Add
BLAST

Sequence similaritiesi

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

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 EPNEEFASRH SLEWKFLFLD HRAPPIIGYL 300
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW 350
LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELS IEESLPEIAA 400
DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS 450
TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS 500
QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK 550
IQEQLQMVHG QGLQMFLQQP NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 600
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP 650
SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ 700
IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT 750
LSVTQQRQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL 800
ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ 846
Length:846
Mass (Da):95,354
Last modified:December 21, 2004 - v1
Checksum:iF7119E879F2C41E2
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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:
EMBL
GenBank
DDBJ
Links Updated
CR859007 mRNA. Translation: CAH91202.1 .
RefSeqi NP_001125706.1. NM_001132234.1.
UniGenei Pab.7567.

3D structure databases

ProteinModelPortali Q5RAK8.
ModBasei Search...
MobiDBi Search...

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 100172630.
KEGGi pon:100172630.

Organism-specific databases

CTDi 9575.

Phylogenomic databases

HOVERGENi HBG050997.
InParanoidi Q5RAK8.
KOi K02223.

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. 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: September 3, 2014
This is version 79 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