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UniProtKB - Q9WVS9 (CLOCK_RAT)

Protein

Circadian locomoter output cycles protein kaput

Gene

Clock

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -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. 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. 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. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence. CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3'. The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. 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. The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis.By similarity

Catalytic activityi

Acetyl-CoA + [protein]-L-lysine = CoA + [protein]-N6-acetyl-L-lysine.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei84Important for interaction with ARNTL/BMAL1By similarity1

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionActivator, DNA-binding, Transferase
Biological processBiological rhythms, DNA damage, Transcription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Circadian locomoter output cycles protein kaput (EC:2.3.1.48)
Short name:
rCLOCK
Gene namesi
Name:Clock
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Rattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620271 Clock

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002626381 – 862Circadian locomoter output cycles protein kaputAdd BLAST862

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei38PhosphoserineBy similarity1
Modified residuei42PhosphoserineBy similarity1
Cross-linki67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity
Modified residuei408PhosphoserineBy similarity1
Modified residuei427Phosphoserine; by GSK3-betaBy similarity1
Modified residuei431PhosphoserineBy similarity1
Modified residuei451Phosphothreonine; by CDK5By similarity1
Modified residuei461Phosphothreonine; by CDK5By similarity1
Cross-linki858Glycyl 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

Proteomic databases

PaxDbiQ9WVS9
PeptideAtlasiQ9WVS9
PRIDEiQ9WVS9

PTM databases

iPTMnetiQ9WVS9
PhosphoSitePlusiQ9WVS9

Expressioni

Tissue specificityi

Expressed in the suprachiasmatic nucleus (SCN), and in the piriform cortex (PC).1 Publication

Inductioni

Without light exposure, high levels at ZT6 and low levels at ZT18 and ZT22. Light exposure increases levels in the SCN in phase dependent manner. Levels increased significantly during the subjective night (ZT10-20). In the piriform cortex, levels increased by light at ZT14.1 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. Forms a heterodimer with ARNTL/BMAL1. The CLOCK-ARNTL/BMAL1 heterodimer 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 RELA/p65. Interacts with KAT2B, CREBBP and EP300. Interacts with ID1 and ID3. Interacts with ID2. Interacts with MTA1. Interacts with OGA. Interacts with SIRT1. Interacts with CIPC. Interacts with EZH2. Interacts with EIF4E, PIWIL1 and DDX4. 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. The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1. Interacts with ASS1 and IMPDH2; in a circadian manner. Interacts with NDUFA9.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei39Interaction with E-box DNABy similarity1
Sitei43Interaction with E-box DNABy similarity1
Sitei47Interaction with E-box DNABy similarity1

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000002976

Structurei

3D structure databases

ProteinModelPortaliQ9WVS9
SMRiQ9WVS9
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini34 – 84bHLHPROSITE-ProRule annotationAdd BLAST51
Domaini107 – 177PAS 1PROSITE-ProRule annotationAdd BLAST71
Domaini262 – 332PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini336 – 379PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni371 – 861Interaction with NR3C1By similarityAdd BLAST491
Regioni450 – 570Interaction with SIRT1By similarityAdd BLAST121
Regioni514 – 564Implicated in the circadian rhythmicityBy similarityAdd BLAST51

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi32 – 47Nuclear localization signalBy similarityAdd BLAST16

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi483 – 844Gln-richAdd BLAST362

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3561 Eukaryota
ENOG410XRJI LUCA
HOGENOMiHOG000234382
HOVERGENiHBG050997
InParanoidiQ9WVS9
KOiK02223
PhylomeDBiQ9WVS9

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q9WVS9-1) [UniParc]FASTAAdd to basket
Also known as: Long, Clock-L

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« 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 IIYVSETVTS LLEHLPSDLV 
       160        170        180        190        200
DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEDLKSKNQ LEFCCHMLRG 
       210        220        230        240        250
TIDPKEPSTY EYVRFIGNFK SLNSVSTSTH NGFEGTIQRT HRPSYEDRVC 
       260        270        280        290        300
FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 
       310        320        330        340        350
PFEVLGTSGY DYYHVDDLES LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW 
       360        370        380        390        400
LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG VEESLPETAA 
       410        420        430        440        450
DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS 
       460        470        480        490        500
TPTKIPTDTS TPPRPHLPAH EKMTQRRSSF SSQSINSQSV GSSLTQPAMS 
       510        520        530        540        550
QAANLPIPQG MSQFQLSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK 
       560        570        580        590        600
IQEQLQMVHG QGLQMFLQQS NPGLNLGSVQ LSSGNSNIQQ LTPINMQGQV 
       610        620        630        640        650
VPVNQIQSGV NAGHVSTGQH MIQQQTLQST STQSQQSVMS GHSQPTSLPN 
       660        670        680        690        700
QTPSTLTAPL YNTMVISQPA AGSMVPIPSS MPQNSTQSAT VTTFTQDRQI 
       710        720        730        740        750
RFSQGQQLVT KLVTAPVACG AVMVPSTMLM GQVVTAYPTF ATQQQQAQAL 
       760        770        780        790        800
SVTQQQQQQQ QQQQQQQQQQ PQQAQQPQSQ QSSQDQPHPS VQQPAQLTQP 
       810        820        830        840        850
PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QQQQLHRHRT 
       860 
DSLTDPSKVQ PQ
Length:862
Mass (Da):97,004
Last modified:November 1, 1999 - v1
Checksum:iD031E4A3758907EC
GO
Isoform 2 (identifier: Q9WVS9-2) [UniParc]FASTAAdd to basket
Also known as: Short, Clock-S

The sequence of this isoform differs from the canonical sequence as follows:
     484-513: Missing.

Show »
Length:832
Mass (Da):93,991
Checksum:i60AD1E3031406FB9
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3V697G3V697_RAT
Circadian locomoter output cycles p...
Clock LOC100911602
864Annotation score:
D4A4R8D4A4R8_RAT
Circadian locomoter output cycles p...
Clock LOC100911602, rCG_56964
833Annotation score:
A0A0G2K8N0A0A0G2K8N0_RAT
Circadian locomoter output cycles p...
Clock rCG_56964
863Annotation score:

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_021795484 – 513Missing in isoform 2. 1 PublicationAdd BLAST30

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB019258 mRNA Translation: BAA81819.1
AB019259 mRNA Translation: BAB68768.1
RefSeqiNP_001276761.1, NM_001289832.1 [Q9WVS9-2]
NP_068628.1, NM_021856.2 [Q9WVS9-1]
UniGeneiRn.205839

Genome annotation databases

GeneIDi60447
KEGGirno:60447
UCSCiRGD:620271 rat [Q9WVS9-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB019258 mRNA Translation: BAA81819.1
AB019259 mRNA Translation: BAB68768.1
RefSeqiNP_001276761.1, NM_001289832.1 [Q9WVS9-2]
NP_068628.1, NM_021856.2 [Q9WVS9-1]
UniGeneiRn.205839

3D structure databases

ProteinModelPortaliQ9WVS9
SMRiQ9WVS9
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000002976

PTM databases

iPTMnetiQ9WVS9
PhosphoSitePlusiQ9WVS9

Proteomic databases

PaxDbiQ9WVS9
PeptideAtlasiQ9WVS9
PRIDEiQ9WVS9

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi60447
KEGGirno:60447
UCSCiRGD:620271 rat [Q9WVS9-1]

Organism-specific databases

CTDi9575
RGDi620271 Clock

Phylogenomic databases

eggNOGiKOG3561 Eukaryota
ENOG410XRJI LUCA
HOGENOMiHOG000234382
HOVERGENiHBG050997
InParanoidiQ9WVS9
KOiK02223
PhylomeDBiQ9WVS9

Miscellaneous databases

PROiPR:Q9WVS9

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiCLOCK_RAT
AccessioniPrimary (citable) accession number: Q9WVS9
Secondary accession number(s): Q920Y1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: November 1, 1999
Last modified: November 7, 2018
This is version 137 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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