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Q5RAK8 (CLOCK_PONAB) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 75. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Circadian locomoter output cycles protein kaput

EC=2.3.1.48
Gene names
Name:CLOCK
OrganismPongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii) [Reference proteome]
Taxonomic identifier9601 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaePongo

Protein attributes

Sequence length846 AA.
Sequence statusComplete.
Protein existenceEvidence at transcript 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 By similarity.

Catalytic activity

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

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 By similarity.

Subcellular location

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 By similarity.

Post-translational modification

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 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.

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
   DomainRepeat
   LigandDNA-binding
   Molecular functionActivator
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to DNA damage stimulus

Inferred from electronic annotation. Source: UniProtKB-KW

circadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of hair cycle

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

spermatogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentchromatoid body

Inferred from sequence or structural similarity. Source: UniProtKB

chromosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

transcription factor complex

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionE-box binding

Inferred from sequence or structural similarity. Source: UniProtKB

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

histone acetyltransferase activity

Inferred from sequence or structural similarity. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

signal transducer activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 846846Circadian locomoter output cycles protein kaput
PRO_0000262637

Regions

Domain34 – 8451bHLH
Domain107 – 17771PAS 1
Domain262 – 33271PAS 2
Domain336 – 37944PAC
Region371 – 845475Interaction with NR3C1 By similarity
Region514 – 56451Implicated in the circadian rhythmicity By similarity
Motif32 – 4716Nuclear localization signal By similarity
Compositional bias483 – 828346Gln-rich

Amino acid modifications

Modified residue381Phosphoserine By similarity
Modified residue421Phosphoserine By similarity
Modified residue4081Phosphoserine By similarity
Modified residue4271Phosphoserine; by GSK3-beta By similarity
Modified residue4511Phosphothreonine; by CDK5 By similarity
Modified residue4611Phosphothreonine; by CDK5 By similarity
Cross-link67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Cross-link842Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity

Sequences

Sequence LengthMass (Da)Tools
Q5RAK8 [UniParc].

Last modified December 21, 2004. Version 1.
Checksum: F7119E879F2C41E2

FASTA84695,354
        10         20         30         40         50         60 
MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 

        70         80         90        100        110        120 
LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG 

       130        140        150        160        170        180 
FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL 

       190        200        210        220        230        240 
TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT 

       250        260        270        280        290        300 
HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFASRH SLEWKFLFLD HRAPPIIGYL 

       310        320        330        340        350        360 
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH 

       370        380        390        400        410        420 
QWNSRPEFIV CTHTVVSYAE VRAERRRELS IEESLPEIAA DKSQDSGSDN RINTVSLKEA 

       430        440        450        460        470        480 
LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF 

       490        500        510        520        530        540 
SSQSINSQSV GSSLTQPVMS QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN 

       550        560        570        580        590        600 
IHRQQEELRK IQEQLQMVHG QGLQMFLQQP NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 

       610        620        630        640        650        660 
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP SQTQSTLTAP 

       670        680        690        700        710        720 
LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ IRFSQGQQLV TKLVTAPVAC 

       730        740        750        760        770        780 
GAVMVPSTML MGQVVTAYPT FATQQQQSQT LSVTQQRQQQ SSQEQQLTSV QQPSQAQLTQ 

       790        800        810        820        830        840 
PPQQFLQTSR LLHGNPSTQL ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP 


SKVQPQ 

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References

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

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
CR859007 mRNA. Translation: CAH91202.1.
RefSeqNP_001125706.1. NM_001132234.1.
UniGenePab.7567.

3D structure databases

ProteinModelPortalQ5RAK8.
ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID100172630.
KEGGpon:100172630.

Organism-specific databases

CTD9575.

Phylogenomic databases

HOVERGENHBG050997.
InParanoidQ5RAK8.
KOK02223.

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...

Entry information

Entry nameCLOCK_PONAB
AccessionPrimary (citable) accession number: Q5RAK8
Entry history
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: December 21, 2004
Last modified: April 16, 2014
This is version 75 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