10         20         30         40         50         60
         |          |          |          |          |          |
MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM - 60
LPGNARKMDK STVLQKSIDF LRKHKETTAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG - 120
FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL - 180
TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLTSVSTSTH NGFEGTIQRT - 240
HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL - 300
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH - 360
QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA - 420
LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMTQRRSSF - 480
SSQSINSQSV GPSLTQPAMS QAANLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN - 540
IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSNIQQ LTPVNMQGQV - 600
VPANQVQSGH ISTGQHMIQQ QTLQSTSTQQ SQQSVMSGHS QQTSLPSQTP STLTAPLYNT - 660
MVISQPAAGS MVQIPSSMPQ NSTQSATVTT FTQDRQIRFS QGQQLVTKLV TAPVACGAVM - 720
VPSTMLMGQV VTAYPTFATQ QQQAQTLSVT QQQQQQQQQP PQQQQQQQQS SQEQQLPSVQ - 780
QPAQAQLGQP PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QPQQQQQLPR - 840
HRTDSLTDPS KVQPQ

Function: ARNTL/2-CLOCK heterodimers activate E-box element (3'- CACGTG-5') transcription of a number of proteins of the circadian clock. Activates transcription of PER1 and PER2. This transcription is inhibited in a feedback loop by PER and CRY proteins. Has intrinsic histone acetyltransferase activity and this enzymatic function contributes to chromatin-remodeling events implicated in circadian control of gene expression. Acetylates primarily histones H3 and H4. Acetylates also a non-histone substrate: its own partner, ARNTL. Plays a role in DNA damage response (DDR) signaling during the S phase.
CATALYTIC ACTIVITY: Acetyl-CoA + [histone] = CoA + acetyl- [histone].
SUBUNIT: Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, ARNTL or ARNTL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerization with ARNTL is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and ARNTL. Interaction with PER and CRY proteins requires translocation to the nucleus. Interaction of the CLOCK-ARNTL heterodimer with PER or CRY inhibits transcription activation. Binds weakly ARNTL and ARNTL2 to form heterodimers which bind poorly to the E-box motif. Q9WTL8:Arntl; NbExp=18; IntAct=EBI-79859, EBI-644534; P97784:Cry1; NbExp=6; IntAct=EBI-79859, EBI-1266607; O54943:Per2; NbExp=9; IntAct=EBI-79859, EBI-1266779; Q923E4:Sirt1; NbExp=11; IntAct=EBI-79859, EBI-1802585;


Subcellular Location: Nucleus. Chromosome. Cytoplasm. Note=Localizes to sites of DNA damage in a H2AX-independent manner (By similarity). Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL-dependent. Phosphorylated form located in the nucleus predominantly between C12 and C21. Nonphosphorylated form found only in the cytoplasm. Event=Alternative splicing; Named isoforms=2; Name=Long; IsoId=O08785-1; Sequence=Displayed; Name=Short; IsoId=O08785-2; Sequence=VSP_002103;
TISSUE SPECIFICITY: Expressed equally in brain, eye, testes, ovaries, liver, heart, lung, kidney. In the brain, expression is abundant in the suprachiasmatic nuclei (SCN), in the pyriform cortex, and in the hippocampus. Low expression throughout the rest of the brain. Expression does not appear to undergo circadian oscillations.
INDUCTION: In the SCN, nuclear expression is lowest between CT7 and CT13. Cytoplasmic expression is highest at these times. In liver, peak levels from CT21 to CT3. Expression of both phosphorylated and unphosphorylated forms of ARNTL with other circadian clock proteins occurs between CT15 and CT18.
DOMAIN: Contains a Gln-rich C-terminal domain which could correspond to the transactivation domain.
PTM: Phosphorylation is dependent on CLOCK-ARNTL heterodimer formation.
POLYMORPHISM: The naturally-occurring CLOCK variant, missing exon 19 (deletion of AA 514-564) due to an A-->T nucleotide transversion in a splice donor site, forms a heterodimer with DNA, but fails to activate transcription. Homozygous CLOCK mutants have a circadian rhythm that is increased from 3 to 4 hours and usually the circadian rhythmicity is lost at constant darkness. Expression of CLOCK is also reduced. There also exists an alternative spliced CLOCK variant missing both exon 18 and exon 19 (AA 484-564).
SIMILARITY: Contains 1 basic helix-loop-helix (bHLH) domain.
SIMILARITY: Contains 1 PAC (PAS-associated C-terminal) domain.
SIMILARITY: Contains 2 PAS (PER-ARNT-SIM) domains.
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