CLOCK_CHICK
ID CLOCK_CHICK Reviewed; 875 AA.
AC Q8QGQ6; Q9W6Q2; Q9W7C3;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 2.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Circadian locomoter output cycles protein kaput;
GN Name=CLOCK;
OS Gallus gallus (Chicken).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae;
OC Phasianinae; Gallus.
OX NCBI_TaxID=9031;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND
RP INDUCTION.
RC TISSUE=Retina;
RX PubMed=10407173; DOI=10.1016/s0169-328x(99)00154-0;
RA Larkin P., Baehr W., Semple-Rowland S.L.;
RT "Circadian regulation of iodopsin and clock is altered in the retinal
RT degeneration chicken retina.";
RL Brain Res. Mol. Brain Res. 70:253-263(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH ARNTL,
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=10931848; DOI=10.1074/jbc.m005671200;
RA Chong N.W., Bernard M., Klein D.C.;
RT "Characterization of the chicken serotonin N-acetyltransferase gene.
RT Activation via clock gene heterodimer/E box interaction.";
RL J. Biol. Chem. 275:32991-32998(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY,
RP INDUCTION, AND INTERACTION WITH ARNTL AND ARNTL2.
RC TISSUE=Pineal gland;
RX PubMed=11554928; DOI=10.1046/j.1365-2443.2001.00462.x;
RA Okano T., Yamamoto K., Okano K., Hirota T., Kasahara T., Sasaki M.,
RA Takanaka Y., Fukada Y.;
RT "Chicken pineal clock genes: implication of BMAL2 as a bidirectional
RT regulator in circadian clock oscillation.";
RL Genes Cells 6:825-836(2001).
RN [4]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=20345751; DOI=10.1111/j.1471-4159.2010.06698.x;
RA Haque R., Ali F.G., Biscoglia R., Abey J., Weller J., Klein D.,
RA Iuvone P.M.;
RT "CLOCK and NPAS2 have overlapping roles in the circadian oscillation of
RT arylalkylamine N-acetyltransferase mRNA in chicken cone photoreceptors.";
RL J. Neurochem. 113:1296-1306(2010).
CC -!- FUNCTION: Transcriptional activator which forms a core component of the
CC circadian clock. The circadian clock, an internal time-keeping system,
CC regulates various physiological processes through the generation of
CC approximately 24 hour circadian rhythms in gene expression, which are
CC translated into rhythms in metabolism and behavior. It is derived from
CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an
CC important regulator of a wide array of physiological functions
CC including metabolism, sleep, body temperature, blood pressure,
CC endocrine, immune, cardiovascular, and renal function. Consists of two
CC major components: the central clock, residing in the suprachiasmatic
CC nucleus (SCN) of the brain, and the peripheral clocks that are present
CC in nearly every tissue and organ system. Both the central and
CC peripheral clocks can be reset by environmental cues, also known as
CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the
CC central clock is light, which is sensed by retina and signals directly
CC to the SCN. The central clock entrains the peripheral clocks through
CC neuronal and hormonal signals, body temperature and feeding-related
CC cues, aligning all clocks with the external light/dark cycle. Circadian
CC rhythms allow an organism to achieve temporal homeostasis with its
CC environment at the molecular level by regulating gene expression to
CC create a peak of protein expression once every 24 hours to control when
CC a particular physiological process is most active with respect to the
CC solar day. Transcription and translation of core clock components
CC (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and
CC CRY2) plays a critical role in rhythm generation, whereas delays
CC imposed by post-translational modifications (PTMs) are important for
CC determining the period (tau) of the rhythms (tau refers to the period
CC of a rhythm and is the length, in time, of one complete cycle). A
CC diurnal rhythm is synchronized with the day/night cycle, while the
CC ultradian and infradian rhythms have a period shorter and longer than
CC 24 hours, respectively. Disruptions in the circadian rhythms contribute
CC to the pathology of cardiovascular diseases, cancer, metabolic
CC syndromes and aging. A transcription/translation feedback loop (TTFL)
CC forms the core of the molecular circadian clock mechanism.
CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2,
CC form the positive limb of the feedback loop, act in the form of a
CC heterodimer and activate the transcription of core clock genes and
CC clock-controlled genes (involved in key metabolic processes), harboring
CC E-box elements (5'-CACGTG-3') within their promoters. The core clock
CC genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form
CC the negative limb of the feedback loop and interact with the
CC CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its
CC activity and thereby negatively regulating their own expression. This
CC heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G,
CC which form a second feedback loop and which activate and repress
CC ARNTL/BMAL1 transcription, respectively. CLOCK regulates the circadian
CC expression of AANAT in the retinal photoreceptor cells. The preferred
CC binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3',
CC which contains a flanking Ala residue in addition to the canonical 6-
CC nucleotide E-box sequence (By similarity). CLOCK specifically binds to
CC the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3'
CC (By similarity). {ECO:0000250|UniProtKB:O08785,
CC ECO:0000269|PubMed:10931848, ECO:0000269|PubMed:11554928,
CC ECO:0000269|PubMed:20345751}.
CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the
CC CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Forms a
CC heterodimer with ARNTL/BMAL1 (PubMed:10931848). The CLOCK-ARNTL/BMAL1
CC heterodimer is required for E-box-dependent transactivation, for CLOCK
CC nuclear translocation and degradation, and for phosphorylation of both
CC CLOCK and ARNTL/BMAL1 (By similarity). Interaction with PER and CRY
CC proteins requires translocation to the nucleus (By similarity).
CC Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY
CC inhibits transcription activation (By similarity). Interacts with
CC ARNTL2/BMAL2 (PubMed:11554928). {ECO:0000250|UniProtKB:O08785,
CC ECO:0000269|PubMed:10931848, ECO:0000269|PubMed:11554928}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O08785}. Nucleus
CC {ECO:0000255|PROSITE-ProRule:PRU00981}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O15516}. Note=Shuttling between the cytoplasm
CC and the nucleus is under circadian regulation and is ARNTL/BMAL1-
CC dependent. {ECO:0000250|UniProtKB:O08785}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8QGQ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8QGQ6-2; Sequence=VSP_021796;
CC -!- TISSUE SPECIFICITY: Expressed in the retinal photoreceptor cells (at
CC protein level). Isoform 1 is expressed in both the retina and pineal
CC gland. Isoform 2 is expressed mainly in the pineal gland.
CC {ECO:0000269|PubMed:10407173, ECO:0000269|PubMed:10931848,
CC ECO:0000269|PubMed:11554928, ECO:0000269|PubMed:20345751}.
CC -!- INDUCTION: Expressed in a circadian rhythm manner in the retina. Levels
CC increase over daylight hours, reaching maximum levels between ZT12 and
CC ZT18. Expression levels continue to oscillate during constant darkness,
CC with levels increasing during subjective day to reach maximum levels
CC between day/night transition. In the pineal gland, shows no robust
CC circadian rhythm with only a slight increase in expression between
CC ZT10-18. {ECO:0000269|PubMed:10407173, ECO:0000269|PubMed:10931848,
CC ECO:0000269|PubMed:11554928, ECO:0000269|PubMed:20345751}.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation.
CC {ECO:0000250|UniProtKB:O08785}.
CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents
CC protein degradation by inhibiting ubiquitination. It also stabilizes
CC the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-
CC mediated transcriptional activation of PER1/2/3 and CRY1/2.
CC {ECO:0000250|UniProtKB:O08785}.
CC -!- PTM: Phosphorylation is dependent on the CLOCK-ARNTL/BMAL1 heterodimer
CC formation. Phosphorylation enhances the transcriptional activity,
CC alters the subcellular localization and decreases the stability of the
CC heterodimer by promoting its degradation.
CC {ECO:0000250|UniProtKB:O08785}.
CC -!- PTM: Sumoylation enhances its transcriptional activity and interaction
CC with ESR1, resulting in up-regulation of ESR1 activity. Estrogen
CC stimulates sumoylation. Desumoylation by SENP1 negatively regulates its
CC transcriptional activity. {ECO:0000250|UniProtKB:O08785}.
CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner
CC in the liver. {ECO:0000250|UniProtKB:O08785}.
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DR EMBL; AF132531; AAD43283.1; -; mRNA.
DR EMBL; AF144425; AAD32860.1; -; mRNA.
DR EMBL; AF246959; AAL98708.1; -; mRNA.
DR RefSeq; NP_001276763.1; NM_001289834.1.
DR RefSeq; NP_989505.2; NM_204174.3.
DR AlphaFoldDB; Q8QGQ6; -.
DR SMR; Q8QGQ6; -.
DR STRING; 9031.ENSGALP00000036747; -.
DR PaxDb; Q8QGQ6; -.
DR PRIDE; Q8QGQ6; -.
DR GeneID; 373991; -.
DR KEGG; gga:373991; -.
DR CTD; 9575; -.
DR VEuPathDB; HostDB:geneid_373991; -.
DR eggNOG; KOG3561; Eukaryota.
DR InParanoid; Q8QGQ6; -.
DR OrthoDB; 205871at2759; -.
DR PhylomeDB; Q8QGQ6; -.
DR PRO; PR:Q8QGQ6; -.
DR Proteomes; UP000000539; Unplaced.
DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0070888; F:E-box binding; IBA:GO_Central.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0051775; P:response to redox state; ISS:UniProtKB.
DR CDD; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR001067; Nuc_translocat.
DR InterPro; IPR001610; PAC.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013767; PAS_fold.
DR Pfam; PF00010; HLH; 1.
DR Pfam; PF00989; PAS; 1.
DR PRINTS; PR00785; NCTRNSLOCATR.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
PE 1: Evidence at protein level;
KW Activator; Alternative splicing; Biological rhythms; Cytoplasm; DNA damage;
KW DNA-binding; Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome;
KW Repeat; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..875
FT /note="Circadian locomoter output cycles protein kaput"
FT /id="PRO_0000262642"
FT DOMAIN 34..84
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 107..177
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 262..332
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 336..379
FT /note="PAC"
FT REGION 420..507
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 516..566
FT /note="Implicated in the circadian rhythmicity"
FT /evidence="ECO:0000250"
FT REGION 628..674
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 794..813
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 842..875
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 32..47
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT COMPBIAS 426..507
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 842..860
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 39
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O15516"
FT SITE 43
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O15516"
FT SITE 47
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O15516"
FT SITE 84
FT /note="Important for interaction with ARNTL/BMAL1"
FT /evidence="ECO:0000250|UniProtKB:O15516"
FT MOD_RES 38
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 42
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 408
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 427
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 451
FT /note="Phosphothreonine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 461
FT /note="Phosphothreonine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT CROSSLNK 67
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT CROSSLNK 871
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT VAR_SEQ 567..585
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10407173,
FT ECO:0000303|PubMed:10931848, ECO:0000303|PubMed:11554928"
FT /id="VSP_021796"
FT CONFLICT 105
FT /note="L -> P (in Ref. 1; AAD43283)"
FT /evidence="ECO:0000305"
FT CONFLICT 160
FT /note="E -> Q (in Ref. 2; AAD32860)"
FT /evidence="ECO:0000305"
FT CONFLICT 217
FT /note="G -> D (in Ref. 1; AAD43283)"
FT /evidence="ECO:0000305"
FT CONFLICT 507
FT /note="L -> H (in Ref. 1; AAD43283)"
FT /evidence="ECO:0000305"
FT CONFLICT 514..517
FT /note="Missing (in Ref. 2; AAD32860)"
FT /evidence="ECO:0000305"
FT CONFLICT 785
FT /note="Q -> QQ (in Ref. 2; AAD32860)"
FT /evidence="ECO:0000305"
FT CONFLICT 796
FT /note="Q -> QQ (in Ref. 3; AAL98708)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 875 AA; 98659 MW; BFC79C9E610DAE1E CRC64;
MFFTISTHKM SSIADRNDGS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM
LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG
FFLAIMTDGN IIYVSESVTP LLEHLPSDLV DQSVFNFIPE GEHSEIYKIL SSHLLESDSL
TPEYLKSKNQ LEFCCHMLRG TIDPKEQPTY EYVKFIGNFK CLNNVPNSAH NGFEGTIQRS
HRPSYEDKVC FIATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL
PFEVLGTSGY DYYHVDDLDN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH
QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPEIKA DKSQDSGSDN HINTVSLKEA
LERFDTSPTP SASSRSSRKS SHTAVSDHSS TPTKMTVDTS TPPRQSLSAH EKSTQRRSSL
SSQSLSSQSL GQPVTQPTMS QPATLQLQSS MSQPVFQFSA QLGAMQHLKD QLEQRTRMIE
ANIHRQQEEL RKIQEQLQIV HGQGLQLSSG PCVPKIHRTD VTVPEMFLQQ STSGLNFSSV
QLTSGNSSSV QQLAPGNMQG QVVQTNQTQS GMNTGHTSTP HMIQQQPLQS SASQHNQQNV
LSGHGQQSSL AGQSQNTVST PLYNTMVISQ PTAGNVVQVP SSLPQNNNQN AAAVTTFTQD
RQIRFSQGQQ LVTKLVTAPV ACGAVMVPST MFMGQVVTAY PTFAAQQQQP QTLPVTQQQQ
QQQQQSQQDQ QQQQQQLTAV QQPAQPQLTQ HPQQFLQTSR LLHGNQSAQL ILSAAFPLQQ
STFTQSHHQQ HQPQQQQLSR HRTDKMTDPS KAQPQ
