ID   CLOCK_NANGA             Reviewed;         865 AA.
AC   Q91YB0;
DT   28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2001, sequence version 1.
DT   27-MAR-2024, entry version 123.
DE   RecName: Full=Circadian locomoter output cycles protein kaput;
DE            EC=2.3.1.48;
GN   Name=Clock;
OS   Nannospalax galili (Northern Israeli blind subterranean mole rat) (Spalax
OS   galili).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC   Spalacidae; Spalacinae; Nannospalax.
OX   NCBI_TaxID=1026970;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH BMAL1, INDUCTION, TISSUE
RP   SPECIFICITY, AND FUNCTION.
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, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a
CC       critical role in rhythm generation, whereas delays imposed by post-
CC       translational modifications (PTMs) are important for determining the
CC       period (tau) of the rhythms (tau refers to the period of a rhythm and
CC       is the length, in time, of one complete cycle). A diurnal rhythm is
CC       synchronized with the day/night cycle, while the ultradian and
CC       infradian rhythms have a period shorter and longer than 24 hours,
CC       respectively. Disruptions in the circadian rhythms contribute to the
CC       pathology of cardiovascular diseases, cancer, metabolic syndromes and
CC       aging. A transcription/translation feedback loop (TTFL) forms the core
CC       of the molecular circadian clock mechanism. Transcription factors,
CC       CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the
CC       feedback loop, act in the form of a heterodimer and activate the
CC       transcription of core clock genes and clock-controlled genes (involved
CC       in key metabolic processes), harboring E-box elements (5'-CACGTG-3')
CC       within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which
CC       are transcriptional repressors form the negative limb of the feedback
CC       loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer
CC       inhibiting its activity and thereby negatively regulating their own
CC       expression. This heterodimer also activates nuclear receptors NR1D1/2
CC       and RORA/B/G, which form a second feedback loop and which activate and
CC       repress 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-BMAL1
CC       heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF,
CC       B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7,
CC       NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated
CC       in glucose and lipid metabolism. Promotes rhythmic chromatin opening,
CC       regulating the DNA accessibility of other transcription factors. The
CC       CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1
CC       and BHLHE40/DEC1 (By similarity). The preferred binding motif for the
CC       CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking
CC       adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-
CC       box sequence (By similarity). CLOCK specifically binds to the half-site
CC       5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (By
CC       similarity). The CLOCK-BMAL1 heterodimer also recognizes the non-
CC       canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an
CC       intrinsic acetyltransferase activity, which enables circadian chromatin
CC       remodeling by acetylating histones and nonhistone proteins, including
CC       its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-
CC       induced transcriptional activity by reducing the association of
CC       NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation
CC       of multiple lysine residues located in its hinge region. The
CC       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       ECO:0000269|PubMed:11707566}.
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, BMAL1 or BMAL2, CSNK1D and/or CSNK1E,
CC       TIMELESS and the PER proteins (By similarity). Forms a heterodimer with
CC       BMAL1 (PubMed:11707566). The CLOCK-BMAL1 heterodimer is required for E-
CC       box-dependent transactivation, for CLOCK nuclear translocation and
CC       degradation, and for phosphorylation of both CLOCK and BMAL1 (By
CC       similarity). Interacts with NR3C1 in a ligand-dependent fashion (By
CC       similarity). Interacts with ESR1 and estrogen stimulates this
CC       interaction (By similarity). Interacts with the complex p35/CDK5 (By
CC       similarity). Interacts with RELA/p65 (By similarity). Interacts with
CC       KAT2B, CREBBP and EP300 (By similarity). Interacts with ID1 and ID3 (By
CC       similarity). Interacts with ID2 (By similarity). Interacts with MTA1
CC       (By similarity). Interacts with OGA (By similarity). Interacts with
CC       SIRT1 (By similarity). Interacts with CIPC (By similarity). Interacts
CC       with EZH2 (By similarity). Interacts with EIF4E, PIWIL1 and DDX4 (By
CC       similarity). Interacts with PER1, PER2, CRY1 and CRY2 and this
CC       interaction requires a translocation to the nucleus (By similarity).
CC       Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits
CC       transcription activation (By similarity). Interaction of the CLOCK-
CC       BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By
CC       similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By
CC       similarity). Interacts with KDM5A (By similarity). Interacts with
CC       KMT2A; in a circadian manner (By similarity). Interacts with MYBBP1A
CC       (By similarity). Interacts with THRAP3 (By similarity). Interacts with
CC       MED1; this interaction requires the presence of THRAP3 (By similarity).
CC       Interacts with NCOA2 (By similarity). The CLOCK-BMAL1 heterodimer
CC       interacts with PASD1. Interacts with ASS1 and IMPDH2; in a circadian
CC       manner. Interacts with NDUFA9 (By similarity). Interacts with PIWIL2
CC       (via PIWI domain) (By similarity). Interacts with HNF4A (By
CC       similarity). {ECO:0000250|UniProtKB:O08785,
CC       ECO:0000250|UniProtKB:O15516, ECO:0000269|PubMed:11707566}.
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 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   -!- TISSUE SPECIFICITY: Expressed in brain, retina and harderian gland as
CC       well as in peripheral tissues, kidney and liver. Localizes in the brain
CC       to the suprachiasmatic nucleus (SCN). {ECO:0000269|PubMed:11707566}.
CC   -!- INDUCTION: Exhibits no circadian rhythm expression.
CC       {ECO:0000269|PubMed:11707566}.
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-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated
CC       transcriptional activation of PER1/2/3 and CRY1/2.
CC       {ECO:0000250|UniProtKB:O08785}.
CC   -!- PTM: Phosphorylation is dependent on the CLOCK-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; AJ318057; CAC85403.1; -; mRNA.
DR   RefSeq; NP_001317029.1; NM_001330100.1.
DR   AlphaFoldDB; Q91YB0; -.
DR   SMR; Q91YB0; -.
DR   GeneID; 103734387; -.
DR   KEGG; ngi:103734387; -.
DR   CTD; 9575; -.
DR   OrthoDB; 2899615at2759; -.
DR   Proteomes; UP000694381; Unplaced.
DR   Proteomes; UP000695027; Unplaced.
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; IDA:MGI.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IEA:InterPro.
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:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR   GO; GO:0006974; P:DNA damage response; IEA:UniProtKB-KW.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; 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:0006355; P:regulation of DNA-templated transcription; 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: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; cd19734; bHLH-PAS_CLOCK; 1.
DR   CDD; cd00130; PAS; 2.
DR   Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1.
DR   Gene3D; 3.30.450.20; PAS domain; 2.
DR   InterPro; IPR011598; bHLH_dom.
DR   InterPro; IPR047230; CLOCK-like.
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   PANTHER; PTHR46055; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 1.
DR   PANTHER; PTHR46055:SF2; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 1.
DR   Pfam; PF00010; HLH; 1.
DR   Pfam; PF00989; PAS; 1.
DR   Pfam; PF14598; PAS_11; 1.
DR   PRINTS; PR00785; NCTRNSLOCATR.
DR   SMART; SM00353; HLH; 1.
DR   SMART; SM00086; PAC; 1.
DR   SMART; SM00091; PAS; 2.
DR   SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1.
DR   SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2.
DR   PROSITE; PS50888; BHLH; 1.
DR   PROSITE; PS50112; PAS; 2.
PE   1: Evidence at protein level;
KW   Activator; Biological rhythms; Cytoplasm; DNA damage; DNA-binding;
KW   Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW   Transcription; Transcription regulation; Transferase; Ubl conjugation.
FT   CHAIN           1..865
FT                   /note="Circadian locomoter output cycles protein kaput"
FT                   /id="PRO_0000262640"
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 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;  97437 MW;  E5003191B7578C21 CRC64;
     MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM
     LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG
     FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSVFNFIPE GEHSEVYKIL STHLLESDSL
     TPEYLKSKNQ LEFCCHMLRG TVDPKEPSTY 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 GPSLTQPVMS 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
//