CLOCK_SPACA
ID CLOCK_SPACA Reviewed; 865 AA.
AC Q91YB2;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 25-MAY-2022, entry version 112.
DE RecName: Full=Circadian locomoter output cycles protein kaput;
DE EC=2.3.1.48;
GN Name=Clock;
OS Spalax carmeli (Southern Israeli blind subterranean mole rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Spalacidae; Spalacinae; Spalax.
OX NCBI_TaxID=164324;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=11707566; DOI=10.1073/pnas.181484498;
RA Avivi A., Albrecht U., Oster H., Joel A., Beiles A., Nevo E.;
RT "Biological clock in total darkness: the Clock/MOP3 circadian system of the
RT blind subterranean mole rat.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:13751-13756(2001).
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. Regulates the circadian
CC expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an
CC enhancer of the transactivation potential of NF-kappaB. Plays an
CC important role in the homeostatic regulation of sleep. The CLOCK-
CC ARNTL/BMAL1 heterodimer regulates the circadian expression of
CC SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A,
CC PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10
CC and also genes implicated in glucose and lipid metabolism. Promotes
CC rhythmic chromatin opening, regulating the DNA accessibility of other
CC transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the
CC transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding
CC motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which
CC contains a flanking Ala residue in addition to the canonical 6-
CC nucleotide E-box sequence. CLOCK specifically binds to the half-site
CC 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3'. The CLOCK-
CC ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs
CC 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an intrinsic
CC acetyltransferase activity, which enables circadian chromatin
CC remodeling by acetylating histones and nonhistone proteins, including
CC its own partner ARNTL/BMAL1. Represses glucocorticoid receptor
CC NR3C1/GR-induced transcriptional activity by reducing the association
CC of NR3C1/GR to glucocorticoid response elements (GREs) via the
CC acetylation of multiple lysine residues located in its hinge region.
CC The acetyltransferase activity of CLOCK is as important as its
CC transcription activity in circadian control. Acetylates metabolic
CC enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1,
CC rhythmically interacts and acetylates argininosuccinate synthase 1
CC (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian
CC oscillation of arginine biosynthesis and subsequent ureagenesis (By
CC similarity). Drives the circadian rhythm of blood pressure through
CC transcriptional activation of ATP1B1 (By similarity).
CC {ECO:0000250|UniProtKB:O08785, ECO:0000250|UniProtKB:O15516}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + L-lysyl-[protein] = CoA + H(+) + N(6)-acetyl-L-
CC lysyl-[protein]; Xref=Rhea:RHEA:45948, Rhea:RHEA-COMP:9752,
CC Rhea:RHEA-COMP:10731, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:61930; EC=2.3.1.48;
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 (By similarity). 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). Interacts with NR3C1 in a
CC ligand-dependent fashion (By similarity). Interacts with ESR1 and
CC estrogen stimulates this interaction (By similarity). Interacts with
CC the complex p35/CDK5 (By similarity). Interacts with RELA/p65 (By
CC similarity). Interacts with KAT2B, CREBBP and EP300 (By similarity).
CC Interacts with ID1 and ID3 (By similarity). Interacts with ID2 (By
CC similarity). Interacts with MTA1 (By similarity). Interacts with OGA
CC (By similarity). Interacts with SIRT1 (By similarity). Interacts with
CC CIPC (By similarity). Interacts with EZH2 (By similarity). Interacts
CC with EIF4E, PIWIL1 and DDX4 (By similarity). Interacts with PER1, PER2,
CC CRY1 and CRY2 and this interaction requires a translocation to the
CC nucleus (By similarity). Interaction of the CLOCK-ARNTL/BMAL1
CC heterodimer with PER or CRY inhibits transcription activation (By
CC similarity). Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is
CC independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-
CC ARNTL/BMAL1 heterodimer interacts with GSK3B (By similarity). Interacts
CC with KDM5A (By similarity). Interacts with KMT2A; in a circadian manner
CC (By similarity). Interacts with MYBBP1A (By similarity). Interacts with
CC THRAP3 (By similarity). Interacts with MED1; this interaction requires
CC the presence of THRAP3 (By similarity). Interacts with NCOA2 (By
CC similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1.
CC Interacts with ASS1 and IMPDH2; in a circadian manner. Interacts with
CC NDUFA9 (By similarity). Interacts with PIWIL2 (via PIWI domain) (By
CC similarity). Interacts with HNF4A (By similarity).
CC {ECO:0000250|UniProtKB:O08785, ECO:0000250|UniProtKB:O15516}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O08785}. Nucleus
CC {ECO:0000255|PROSITE-ProRule:PRU00981}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O15516}. Note=Localizes to sites of DNA damage
CC in a H2AX-independent manner. Shuttling between the cytoplasm and the
CC nucleus is under circadian regulation and is ARNTL/BMAL1-dependent.
CC Phosphorylated form located in the nucleus while the nonphosphorylated
CC form found only in the cytoplasm. Sequestered to the cytoplasm in the
CC presence of ID2. {ECO:0000250|UniProtKB:O08785,
CC ECO:0000250|UniProtKB:O15516}.
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; AJ318058; CAC85404.1; -; mRNA.
DR AlphaFoldDB; Q91YB2; -.
DR SMR; Q91YB2; -.
DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB.
DR GO; GO:0004402; F:histone acetyltransferase activity; ISS:UniProtKB.
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; ISS: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; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0042634; P:regulation of hair cycle; ISS:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:2000074; P:regulation of type B pancreatic cell development; ISS:UniProtKB.
DR GO; GO:0051775; P:response to redox state; ISS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; 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 2: Evidence at transcript level;
KW Activator; Biological rhythms; Cytoplasm; DNA damage; DNA-binding;
KW Isopeptide bond; Nucleus; Phosphoprotein; Repeat; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1..865
FT /note="Circadian locomoter output cycles protein kaput"
FT /id="PRO_0000262639"
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 371..864
FT /note="Interaction with NR3C1"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT REGION 420..494
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 450..570
FT /note="Interaction with SIRT1"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT REGION 514..564
FT /note="Implicated in the circadian rhythmicity"
FT /evidence="ECO:0000250"
FT REGION 620..653
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 755..803
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 822..865
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 427..464
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 475..494
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 431
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08785"
FT MOD_RES 451
FT /note="Phosphothreonine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:O15516"
FT MOD_RES 461
FT /note="Phosphothreonine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:O15516"
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 861
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:O08785"
SQ SEQUENCE 865 AA; 97419 MW; CA58A56F535C6625 CRC64;
MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM
LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG
FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSVFNFIPE GEHSEVYKIL STHLLESDSL
TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLNSVPTSAH NGFEGTIQRT
HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH
QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPDAAA DKSQDSGSDN RINTVSLKEA
LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMAQRRSSF
SSQSMNSQSV GPSLTQPVIS QAANLPVPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN
IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLTPINMQGQ
VVPTNQIQSG MNAGHIGTSQ HLIQQQSLQS TSTQQSQQSV MSGHSQQTSL ASQTQSTLTA
PLYNTMVISQ PAPGSMVQIP SSMPQNSTQS ATVTTFTQDR QIRFSQGQQL VTKLVTAPVA
CGAVMVPSTM LMGQVVTAYP TFATQQQQAQ TLSVTQQQPQ QQQPQQQQPQ QQQPQQQQQS
SQEQQLPSVP QPSQAQLTQS PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH
QSQQQQQLSR HRTDSLTDPS KVQPQ
