UniProtKB - Q9WVS9 (CLOCK_RAT)
Circadian locomoter output cycles protein kaput
Clock
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).
Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity).
By similarityCatalytic activityi
- EC:2.3.1.48
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 84 | Important for interaction with ARNTL/BMAL1By similarity | 1 |
GO - Molecular functioni
- chromatin DNA binding Source: UniProtKB
- DNA binding Source: UniProtKB
- DNA-binding transcription activator activity, RNA polymerase II-specific Source: RGD
- DNA-binding transcription factor activity Source: UniProtKB
- DNA-binding transcription factor activity, RNA polymerase II-specific Source: RGD
- E-box binding Source: UniProtKB
- histone acetyltransferase activity Source: UniProtKB
- protein dimerization activity Source: InterPro
- RNA polymerase II cis-regulatory region sequence-specific DNA binding Source: UniProtKB
- sequence-specific DNA binding Source: UniProtKB
- sequence-specific double-stranded DNA binding Source: RGD
GO - Biological processi
- cellular response to ionizing radiation Source: RGD
- circadian regulation of gene expression Source: UniProtKB
- circadian rhythm Source: RGD
- DNA damage checkpoint signaling Source: RGD
- entrainment of circadian clock Source: RGD
- female pregnancy Source: RGD
- negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
- negative regulation of transcription, DNA-templated Source: UniProtKB
- positive regulation of circadian rhythm Source: RGD
- positive regulation of inflammatory response Source: RGD
- positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
- positive regulation of transcription, DNA-templated Source: UniProtKB
- positive regulation of transcription by RNA polymerase II Source: RGD
- proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
- protein acetylation Source: UniProtKB
- regulation of circadian rhythm Source: UniProtKB
- regulation of hair cycle Source: UniProtKB
- regulation of insulin secretion Source: UniProtKB
- regulation of transcription, DNA-templated Source: UniProtKB
- regulation of transcription by RNA polymerase II Source: GO_Central
- regulation of type B pancreatic cell development Source: UniProtKB
- response to light stimulus Source: RGD
- response to redox state Source: UniProtKB
- spermatogenesis Source: UniProtKB
Keywordsi
Molecular function | Activator, DNA-binding, Transferase |
Biological process | Biological rhythms, DNA damage, Transcription, Transcription regulation |
Names & Taxonomyi
Protein namesi | |
Gene namesi | Name:Clock |
Organismi | Rattus norvegicus (Rat) |
Taxonomic identifieri | 10116 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Rattus |
Proteomesi |
|
Organism-specific databases
RGDi | 620271, Clock |
Subcellular locationi
Nucleus
- Nucleus PROSITE-ProRule annotation
Cytoplasm and Cytosol
Note: Localizes to sites of DNA damage in a H2AX-independent manner. Shuttling 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
Cytosol
- cytosol Source: UniProtKB
Endoplasmic reticulum
- rough endoplasmic reticulum Source: RGD
Nucleus
- CLOCK-BMAL transcription complex Source: RGD
- nucleolus Source: RGD
- nucleus Source: UniProtKB
- perichromatin fibrils Source: RGD
Other locations
- chromatoid body Source: UniProtKB
- chromosome Source: RGD
- cytoplasm Source: RGD
- transcription regulator complex Source: UniProtKB
Keywords - Cellular componenti
Cytoplasm, NucleusPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000262638 | 1 – 862 | Circadian locomoter output cycles protein kaputAdd BLAST | 862 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 38 | PhosphoserineBy similarity | 1 | |
Modified residuei | 42 | PhosphoserineBy similarity | 1 | |
Cross-linki | 67 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity | ||
Modified residuei | 408 | PhosphoserineBy similarity | 1 | |
Modified residuei | 427 | Phosphoserine; by GSK3-betaBy similarity | 1 | |
Modified residuei | 431 | PhosphoserineBy similarity | 1 | |
Modified residuei | 451 | Phosphothreonine; by CDK5By similarity | 1 | |
Modified residuei | 461 | Phosphothreonine; by CDK5By similarity | 1 | |
Cross-linki | 858 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity |
Post-translational modificationi
Keywords - PTMi
Isopeptide bond, Phosphoprotein, Ubl conjugationProteomic databases
PaxDbi | Q9WVS9 |
PeptideAtlasi | Q9WVS9 |
PRIDEi | Q9WVS9 |
PTM databases
iPTMneti | Q9WVS9 |
PhosphoSitePlusi | Q9WVS9 |
Expressioni
Tissue specificityi
Inductioni
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 (By similarity).
Forms a heterodimer with ARNTL/BMAL1 (By similarity). 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 (By similarity).
Interacts with NR3C1 in a ligand-dependent fashion (By similarity).
Interacts with ESR1 and estrogen stimulates this interaction (By similarity).
Interacts with the complex p35/CDK5 (By similarity).
Interacts with RELA/p65 (By similarity).
Interacts with KAT2B, CREBBP and EP300 (By similarity).
Interacts with ID1 and ID3 (By similarity).
Interacts with ID2 (By similarity).
Interacts with MTA1 (By similarity).
Interacts with OGA (By similarity).
Interacts with SIRT1 (By similarity).
Interacts with CIPC (By similarity).
Interacts with EZH2 (By similarity).
Interacts with EIF4E, PIWIL1 and DDX4 (By similarity).
Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B (By similarity).
Interacts with KDM5A (By similarity).
Interacts with KMT2A; in a circadian manner (By similarity).
Interacts with MYBBP1A (By similarity).
Interacts with THRAP3 (By similarity).
Interacts with MED1; this interaction requires the presence of THRAP3 (By similarity).
Interacts with NCOA2 (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1.
Interacts with ASS1 and IMPDH2; in a circadian manner.
Interacts with NDUFA9 (By similarity).
Interacts with PIWIL2 (via PIWI domain) (By similarity).
Interacts with HNF4A (By similarity).
By similaritySites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 39 | Interaction with E-box DNABy similarity | 1 | |
Sitei | 43 | Interaction with E-box DNABy similarity | 1 | |
Sitei | 47 | Interaction with E-box DNABy similarity | 1 |
GO - Molecular functioni
- protein dimerization activity Source: InterPro
Protein-protein interaction databases
STRINGi | 10116.ENSRNOP00000002976 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 34 – 84 | bHLHPROSITE-ProRule annotationAdd BLAST | 51 | |
Domaini | 107 – 177 | PAS 1PROSITE-ProRule annotationAdd BLAST | 71 | |
Domaini | 262 – 332 | PAS 2PROSITE-ProRule annotationAdd BLAST | 71 | |
Domaini | 336 – 379 | PACAdd BLAST | 44 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 371 – 861 | Interaction with NR3C1By similarityAdd BLAST | 491 | |
Regioni | 388 – 497 | DisorderedSequence analysisAdd BLAST | 110 | |
Regioni | 450 – 570 | Interaction with SIRT1By similarityAdd BLAST | 121 | |
Regioni | 514 – 564 | Implicated in the circadian rhythmicityBy similarityAdd BLAST | 51 | |
Regioni | 623 – 652 | DisorderedSequence analysisAdd BLAST | 30 | |
Regioni | 768 – 802 | DisorderedSequence analysisAdd BLAST | 35 | |
Regioni | 822 – 862 | DisorderedSequence analysisAdd BLAST | 41 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 32 – 47 | Nuclear localization signalBy similarityAdd BLAST | 16 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 400 – 415 | Polar residuesSequence analysisAdd BLAST | 16 | |
Compositional biasi | 427 – 457 | Polar residuesSequence analysisAdd BLAST | 31 | |
Compositional biasi | 474 – 497 | Polar residuesSequence analysisAdd BLAST | 24 | |
Compositional biasi | 822 – 840 | Polar residuesSequence analysisAdd BLAST | 19 |
Keywords - Domaini
RepeatPhylogenomic databases
eggNOGi | KOG3561, Eukaryota |
InParanoidi | Q9WVS9 |
PhylomeDBi | Q9WVS9 |
Family and domain databases
CDDi | cd00130, PAS, 2 hits |
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00010, HLH, 1 hit PF00989, PAS, 1 hit |
PRINTSi | PR00785, NCTRNSLOCATR |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00086, PAC, 1 hit SM00091, PAS, 2 hits |
SUPFAMi | SSF47459, SSF47459, 1 hit SSF55785, SSF55785, 2 hits |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS50112, PAS, 2 hits |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
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
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A0G2K8N0 | A0A0G2K8N0_RAT | Circadian locomoter output cycles p... | Clock | 864 | Annotation score: | ||
D4A4R8 | D4A4R8_RAT | Circadian locomoter output cycles p... | Clock LOC100911602 | 850 | Annotation score: |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_021795 | 484 – 513 | Missing in isoform 2. 1 PublicationAdd BLAST | 30 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AB019258 mRNA Translation: BAA81819.1 AB019259 mRNA Translation: BAB68768.1 |
RefSeqi | NP_001276761.1, NM_001289832.1 [Q9WVS9-2] NP_068628.1, NM_021856.2 [Q9WVS9-1] |
Genome annotation databases
GeneIDi | 60447 |
KEGGi | rno:60447 |
UCSCi | RGD:620271, rat [Q9WVS9-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AB019258 mRNA Translation: BAA81819.1 AB019259 mRNA Translation: BAB68768.1 |
RefSeqi | NP_001276761.1, NM_001289832.1 [Q9WVS9-2] NP_068628.1, NM_021856.2 [Q9WVS9-1] |
3D structure databases
AlphaFoldDBi | Q9WVS9 |
SMRi | Q9WVS9 |
ModBasei | Search... |
Protein-protein interaction databases
STRINGi | 10116.ENSRNOP00000002976 |
PTM databases
iPTMneti | Q9WVS9 |
PhosphoSitePlusi | Q9WVS9 |
Proteomic databases
PaxDbi | Q9WVS9 |
PeptideAtlasi | Q9WVS9 |
PRIDEi | Q9WVS9 |
Genome annotation databases
GeneIDi | 60447 |
KEGGi | rno:60447 |
UCSCi | RGD:620271, rat [Q9WVS9-1] |
Organism-specific databases
CTDi | 9575 |
RGDi | 620271, Clock |
Phylogenomic databases
eggNOGi | KOG3561, Eukaryota |
InParanoidi | Q9WVS9 |
PhylomeDBi | Q9WVS9 |
Miscellaneous databases
PROi | PR:Q9WVS9 |
Family and domain databases
CDDi | cd00130, PAS, 2 hits |
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00010, HLH, 1 hit PF00989, PAS, 1 hit |
PRINTSi | PR00785, NCTRNSLOCATR |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00086, PAC, 1 hit SM00091, PAS, 2 hits |
SUPFAMi | SSF47459, SSF47459, 1 hit SSF55785, SSF55785, 2 hits |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS50112, PAS, 2 hits |
MobiDBi | Search... |
Entry informationi
Entry namei | CLOCK_RAT | |
Accessioni | Q9WVS9Primary (citable) accession number: Q9WVS9 Secondary accession number(s): Q920Y1 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 28, 2006 |
Last sequence update: | November 1, 1999 | |
Last modified: | May 25, 2022 | |
This is version 152 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |