Reviewed, UniProtKB/Swiss-Prot O08785 (CLOCK_MOUSE)

Names and origin

Protein names

Recommended name:
    Circadian locomoter output cycles protein kaput
      Short name=mCLOCK
    EC=2.3.1.48

Gene names

Name:

Clock

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	855 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

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. Ref.8
Catalytic activity	Acetyl-CoA + histone = CoA + acetylhistone.
Subunit structure	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.
Subcellular location	Cytoplasm. Nucleus. Note: 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. Ref.5 Ref.6
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. Ref.2
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. Ref.5 Ref.6
Domain	Contains a Gln-rich C-terminal domain which could correspond to the transactivation domain.
Post-translational modification	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).
Sequence similarities	Contains 1 basic helix-loop-helix (bHLH) domain. Contains 1 PAC (PAS-associated C-terminal) domain. Contains 2 PAS (PER-ARNT-SIM) domains.

Ontologies

Keywords
Biological process	Biological rhythms Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator Acyltransferase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	circadian rhythm Ref.6 Inferred from direct assay. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from genetic interaction. Source: MGI signal transduction Inferred from electronic annotation. Source: InterPro transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Ref.6 Inferred from direct assay. Source: MGI transcription factor complex Inferred from direct assay. Source: MGI
Molecular function	histone acetyltransferase activity Inferred from electronic annotation. Source: EC protein binding Inferred from physical interaction. Source: IntAct signal transducer activity Inferred from electronic annotation. Source: InterPro transcription factor activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Arntl	Q9WTL8	1	EBI-79859,EBI-644534
Per2	O54943	3	EBI-79859,EBI-1266779
Sirt1	Q923E4	4	EBI-79859,EBI-1802585

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: O08785-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: O08785-2)

The sequence of this isoform differs from the canonical sequence as follows:
     484-513: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 855	855	Circadian locomoter output cycles protein kaput		PRO_0000127164
Regions
	Domain	48 – 85	38	Helix-loop-helix motif
	Domain	107 – 177	71	PAS 1
	Domain	262 – 332	71	PAS 2
	Domain	336 – 379	44	PAC
	DNA binding	35 – 47	13	Basic motif
	Region	514 – 564	51	Implicated in the circadian rhythmicity
	Compositional bias	484 – 855	372	Gln-rich
	Compositional bias	740 – 745	6	Poly-Gln
	Compositional bias	751 – 759	9	Poly-Gln
	Compositional bias	762 – 769	8	Poly-Gln
	Compositional bias	828 – 837	10	Poly-Gln
Amino acid modifications
	Modified residue	408	1	Phosphoserine Ref.9
Natural variations
	Alternative sequence	484 – 513	30	Missing in isoform Short.		VSP_002103
Experimental info
	Mutagenesis	656	1	P → A: Reduces histone acetyltransferase activity; when associated with A-658 and A-659. Ref.7
	Mutagenesis	658	1	Y → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-659. Ref.7
	Mutagenesis	659	1	N → A: Reduces histone acetyltransferase activity; when associated with A-656 and A-658. Ref.7
	Mutagenesis	669	1	G → A: Reduces histone acetyltransferase activity; when associated with A-670 and A-672. Ref.7
	Mutagenesis	670	1	S → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-672. Ref.7
	Mutagenesis	672	1	V → A: Reduces histone acetyltransferase activity; when associated with A-669 and A-670. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified July 1, 1997. Version 1. Checksum: 9864D947049742F4	FASTA	855	96,393
	10 20 30 40 50 60 MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 70 80 90 100 110 120 LPGNARKMDK STVLQKSIDF LRKHKETTAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG 130 140 150 160 170 180 FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL 190 200 210 220 230 240 TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLTSVSTSTH NGFEGTIQRT 250 260 270 280 290 300 HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 310 320 330 340 350 360 PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH 370 380 390 400 410 420 QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA 430 440 450 460 470 480 LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMTQRRSSF 490 500 510 520 530 540 SSQSINSQSV GPSLTQPAMS QAANLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN 550 560 570 580 590 600 IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSNIQQ LTPVNMQGQV 610 620 630 640 650 660 VPANQVQSGH ISTGQHMIQQ QTLQSTSTQQ SQQSVMSGHS QQTSLPSQTP STLTAPLYNT 670 680 690 700 710 720 MVISQPAAGS MVQIPSSMPQ NSTQSATVTT FTQDRQIRFS QGQQLVTKLV TAPVACGAVM 730 740 750 760 770 780 VPSTMLMGQV VTAYPTFATQ QQQAQTLSVT QQQQQQQQQP PQQQQQQQQS SQEQQLPSVQ 790 800 810 820 830 840 QPAQAQLGQP PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QPQQQQQLPR 850 HRTDSLTDPS KVQPQ
	Isoform Short. Checksum: FABAE927F765B680	FASTA	825	93,371
	10 20 30 40 50 60 MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 70 80 90 100 110 120 LPGNARKMDK STVLQKSIDF LRKHKETTAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG 130 140 150 160 170 180 FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL 190 200 210 220 230 240 TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLTSVSTSTH NGFEGTIQRT 250 260 270 280 290 300 HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL 310 320 330 340 350 360 PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH 370 380 390 400 410 420 QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA 430 440 450 460 470 480 LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMTQRRSSF 490 500 510 520 530 540 SSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK IQEQLQMVHG QGLQMFLQQS 550 560 570 580 590 600 NPGLNFGSVQ LSSGNSNIQQ LTPVNMQGQV VPANQVQSGH ISTGQHMIQQ QTLQSTSTQQ 610 620 630 640 650 660 SQQSVMSGHS QQTSLPSQTP STLTAPLYNT MVISQPAAGS MVQIPSSMPQ NSTQSATVTT 670 680 690 700 710 720 FTQDRQIRFS QGQQLVTKLV TAPVACGAVM VPSTMLMGQV VTAYPTFATQ QQQAQTLSVT 730 740 750 760 770 780 QQQQQQQQQP PQQQQQQQQS SQEQQLPSVQ QPAQAQLGQP PQQFLQTSRL LHGNPSTQLI 790 800 810 820 LSAAFPLQQS TFPPSHHQQH QPQQQQQLPR HRTDSLTDPS KVQPQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Functional identification of the mouse circadian clock gene by transgenic BAC rescue." Antoch M.P., Song E.J., Chang A.M., Vitaterna M.H., Zhao Y., Wilsbacher L.D., Sangoram A.M., King D.P., Pinto L.H., Takahashi J.S. Cell 89:655-667(1997) [PubMed: 9160756] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG). Strain: 129.
[2]	"Positional cloning of the mouse circadian clock gene." King D.P., Zhao Y., Sangoram A.M., Wilsbacher L.D., Tanaka M., Antoch M.P., Steeves T.D.L., Vitaterna M.H., Kornhauser J.M., Lowrey P.L., Turek F.W., Takahashi J.S. Cell 89:641-653(1997) [PubMed: 9160755] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS LONG AND SHORT), TISSUE SPECIFICITY, IDENTIFICATION OF CLOCK VARIANT. Strain: C57BL/6 X BALB/c. Tissue: Suprachiasmatic nucleus.
[3]	"The mouse Clock locus: sequence and comparative analysis of 204 kb from mouse chromosome 5." Wilsbacher L.D., Sangoram A.M., Antoch M.P., Takahashi J.S. Genome Res. 10:1928-1940(2000) [PubMed: 11116088] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129/Sv.
[4]	"Role of the CLOCK protein in the mammalian circadian mechanism." Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D., King D.P., Takahashi J.S., Weitz C.J. Science 280:1564-1569(1998) [PubMed: 9616112] [Abstract] Cited for: INTERACTION WITH ARNTL.
[5]	"Posttranslational mechanisms regulate the mammalian circadian clock." Lee C., Etchegaray J.-P., Cagampang F.R.A., Loudon A.S.I., Reppert S.M. Cell 107:855-867(2001) [PubMed: 11779462] [Abstract] Cited for: INTERACTION WITH ARNTL; PER1; PER2; CRY1; CRY2 AND CSNK1E, PHOSPHORYLATION, SUBCELLULAR LOCATION, INDUCTION.
[6]	"BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system." Kondratov R.V., Chernov M.V., Kondratova A.A., Gorbacheva V.Y., Gudkov A.V., Antoch M.P. Genes Dev. 17:1921-1932(2003) [PubMed: 12897057] [Abstract] Cited for: INTERACTION WITH ARNTL, PHOSPHORYLATION, SUBCELLULAR LOCATION, INDUCTION.
[7]	"Circadian regulator CLOCK is a histone acetyltransferase." Doi M., Hirayama J., Sassone-Corsi P. Cell 125:497-508(2006) [PubMed: 16678094] [Abstract] Cited for: HISTONE ACETYLTRANSFERASE ACTIVITY, MUTAGENESIS OF PRO-656; TYR-658; ASN-659; GLY-669; SER-670 AND VAL-672.
[8]	"CLOCK-mediated acetylation of BMAL1 controls circadian function." Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K., Nakahata Y., Sassone-Corsi P. Nature 450:1086-1090(2007) [PubMed: 18075593] [Abstract] Cited for: FUNCTION IN ACETYLATION OF ARNTL.
[9]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-408, MASS SPECTROMETRY. Tissue: Liver.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF000998 mRNA. Translation: AAC53200.1. AF146793 Genomic DNA. Translation: AAD30565.1.
IPI	IPI00230536. IPI00420596.
RefSeq	NP_031741.1.
UniGene	Mm.3552 Mm.392894
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	O08785. 8 interactions.
STRING	O08785.
PTM databases
PhosphoSite	O08785.
Proteomic databases
PRIDE	O08785.
Genome annotation databases
Ensembl	ENSMUST00000031148; ENSMUSP00000031148; ENSMUSG00000029238; Mus musculus. [Genome view] ENSMUST00000075159; ENSMUSP00000074656; ENSMUSG00000029238; Mus musculus. [Genome view] ENSMUST00000113497; ENSMUSP00000109125; ENSMUSG00000029238; Mus musculus. [Genome view] ENSMUST00000113499; ENSMUSP00000109127; ENSMUSG00000029238; Mus musculus. [Genome view]
GeneID	12753.
KEGG	mmu:12753.
UCSC	uc008xuq.1. mouse.
Organism-specific databases
CTD	12753.
MGI	MGI:99698. Clock.
Phylogenomic databases
HOVERGEN	O08785.
Enzyme and pathway databases
BRENDA	2.3.1.48. 244.
Gene expression databases
ArrayExpress	O08785.
Bgee	O08785.
CleanEx	MM_CLOCK.
Genevestigator	O08785.
GermOnline	ENSMUSG00000029238. Mus musculus.
Family and domain databases
InterPro	IPR001092. HLH_basic. IPR011598. HLH_DNA_bd. IPR001067. Nuc_translocat. IPR001610. PAC. IPR000014. PAS. IPR013767. PAS_fold. IPR013655. PAS_fold_3. [Graphical view]
Gene3D	G3DSA:4.10.280.10. HLH_DNA_bd. 1 hit.
Pfam	PF00010. HLH. 1 hit. PF00989. PAS. 1 hit. PF08447. PAS_3. 1 hit. [Graphical view]
PRINTS	PR00785. NCTRNSLOCATR.
SMART	SM00353. HLH. 1 hit. SM00086. PAC. 1 hit. SM00091. PAS. 2 hits. [Graphical view]
PROSITE	PS50888. HLH. 1 hit. PS50113. PAC. False negative. PS50112. PAS. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	282092.
SOURCE	Search...

Entry information

Entry name

CLOCK_MOUSE

Accession

Primary (citable) accession number: O08785

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	July 1, 1997
Last modified:	October 13, 2009
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)