O15516 (CLOCK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Alternative name(s):
Class E basic helix-loop-helix protein 8
Short name=bHLHe8

Gene names

Name:	CLOCK
Synonyms:	BHLHE8, KIAA0334

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	846 AA.
Sequence status	Complete.
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 By similarity. Acetylates primarily histones H3 and H4 By similarity. Acetylates also a non-histone substrate: ARNTL By similarity. Plays a role in DNA damage response (DDR) signaling during the S phase. Ref.9
Catalytic activity	Acetyl-CoA + [histone] = CoA + acetyl-[histone].
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 By similarity.
Subcellular location	Nucleus. Chromosome. Cytoplasm By similarity. Nucleus By similarity. Note: Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL-dependent. Phosphorylated form located in the nucleus By similarity. Localizes to sites of DNA damage in a H2AX-independent manner. Ref.9
Tissue specificity	Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in testis and skeletal muscle. Low levels in thymus, lung and liver. Expressed in all brain regions with highest levels in cerebellum. Highly expressed in the suprachiasmatic nucleus (SCN). Ref.1
Post-translational modification	Phosphorylation is dependent on CLOCK-ARNTL heterodimer formation By similarity.
Miscellaneous	CLOCK-ARNTL double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-ARNTL transcriptional activity of PER1 and disrupt circadian rhythmicity.
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.
Sequence caution	The sequence BAA20792.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Biological rhythms DNA damage Transcription Transcription regulation
Cellular component	Chromosome Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator Acyltransferase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	DNA damage checkpoint Inferred from mutant phenotype Ref.9. Source: UniProtKB cellular response to ionizing radiation Inferred from direct assay Ref.9. Source: UniProtKB circadian regulation of gene expression Inferred from sequence or structural similarity. Source: BHF-UCL photoperiodism Traceable author statement. Source: ProtInc
Cellular component	chromosome Inferred from direct assay Ref.9. Source: UniProtKB cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell transcription factor complex Inferred from physical interaction. Source: MGI
Molecular function	E-box binding Inferred from direct assay. Source: BHF-UCL RNA polymerase II core promoter proximal region sequence-specific DNA binding Inferred from direct assay. Source: BHF-UCL RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: BHF-UCL RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription Inferred from sequence or structural similarity. Source: BHF-UCL histone acetyltransferase activity Inferred from electronic annotation. Source: EC signal transducer activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 846	846	Circadian locomoter output cycles protein kaput		PRO_0000127163
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 By similarity
	Compositional bias	744 – 760	17	Gln-rich
	Compositional bias	819 – 828	10	Poly-Gln
Amino acid modifications
	Modified residue	331	1	Phosphotyrosine Ref.8
	Modified residue	408	1	Phosphoserine By similarity
Natural variations
	Natural variant	208	1	S → C. Corresponds to variant rs34897046 [ dbSNP | Ensembl ].		VAR_040061
	Natural variant	380	1	E → K. Corresponds to variant rs1056478 [ dbSNP | Ensembl ].		VAR_040062
	Natural variant	395	1	L → I. Corresponds to variant rs6855837 [ dbSNP | Ensembl ].		VAR_029076
	Natural variant	542	1	H → R. Corresponds to variant rs3762836 [ dbSNP | Ensembl ].		VAR_029077
Experimental info
	Mutagenesis	116	1	E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with K-367 and L-601. Ref.7
	Mutagenesis	332	1	G → E: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with L-840. Ref.7
	Mutagenesis	360	1	H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity. Ref.7
	Mutagenesis	367	1	E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition CLOCK-ARNTL transcriptional activity; when associated with E-116 and L-601. Ref.7
	Mutagenesis	601	1	V → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with K-116 and K-367. Ref.7
	Mutagenesis	840	1	P → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity; when associated with E-332. Ref.7
	Sequence conflict	440	1	S → P in AAF13733. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O15516 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: C292B451A33E4CBF	FASTA	846	95,304
	10 20 30 40 50 60 MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM 70 80 90 100 110 120 LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG 130 140 150 160 170 180 FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL 190 200 210 220 230 240 TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH 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 EKMVQRRSSF 490 500 510 520 530 540 SSQSINSQSV GSSLTQPVMS QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN 550 560 570 580 590 600 IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ 610 620 630 640 650 660 VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP SQTQSTLTAP 670 680 690 700 710 720 LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ IRFSQGQQLV TKLVTAPVAC 730 740 750 760 770 780 GAVMVPSTML MGQVVTAYPT FATQQQQSQT LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ 790 800 810 820 830 840 PPQQFLQTSR LLHGNPSTQL ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei." Steeves T.D.L., King D.P., Zhao Y., Sangoram A.M., Du F., Bowcock A.M., Moore R.Y., Takahashi J.S. Genomics 57:189-200(1999) [PubMed: 10198158] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], TISSUE SPECIFICITY.
[2]	NHLBI resequencing and genotyping service (RS&G) Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 4:141-150(1997) [PubMed: 9205841] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[6]	"Molecular cloning of human Clock cDNA 5'-end." Ikeda M., Takehara N., Ebisawa T., Yamauchi T., Nomura M. Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-349. Tissue: Brain.
[7]	"Feedback repression is required for mammalian circadian clock function." Sato T.K., Yamada R.G., Ukai H., Baggs J.E., Miraglia L.J., Kobayashi T.J., Welsh D.K., Kay S.A., Ueda H.R., Hogenesch J.B. Nat. Genet. 38:312-319(2006) [PubMed: 16474406] [Abstract] Cited for: MUTAGENESIS OF GLU-116; GLY-332; HIS-360; GLU-367; VAL-601 AND PRO-840.
[8]	"An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells." Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., Wiley H.S., Qian W.-J. J. Proteome Res. 8:3852-3861(2009) [PubMed: 19534553] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-331, MASS SPECTROMETRY. Tissue: Mammary epithelium.
[9]	"A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling." Cotta-Ramusino C., McDonald E.R. III, Hurov K., Sowa M.E., Harper J.W., Elledge S.J. Science 332:1313-1317(2011) [PubMed: 21659603] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF011568 mRNA. Translation: AAB83969.1. AF097458 , AF097442, AF097443, AF097444, AF097445, AF097446, AF097447, AF097448, AF097449, AF097450, AF097451, AF097452, AF097453, AF097454, AF097455, AF097456, AF097457 Genomic DNA. Translation: AAF13733.1. EF015897 Genomic DNA. Translation: ABM64208.1. AB002332 mRNA. Translation: BAA20792.2. Different initiation. AK291708 mRNA. Translation: BAF84397.1. BC126157 mRNA. Translation: AAI26158.1. BC126159 mRNA. Translation: AAI26160.1. AB005535 mRNA. Translation: BAA21774.1.
IPI	IPI00007284.
RefSeq	NP_004889.1. NM_004898.2.
UniGene	Hs.436975.
3D structure databases
ProteinModelPortal	O15516.
SMR	O15516. Positions 47-85, 114-171, 272-380.
ModBase	Search...
Protein-protein interaction databases
IntAct	O15516. 3 interactions.
STRING	O15516.
PTM databases
PhosphoSite	O15516.
Proteomic databases
PRIDE	O15516.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000309964; ENSP00000308741; ENSG00000134852. ENST00000381322; ENSP00000370723; ENSG00000134852.
GeneID	9575.
KEGG	hsa:9575.
UCSC	uc003haz.1. human.
Organism-specific databases
CTD	9575.
GeneCards	GC04M056294.
H-InvDB	HIX0004226.
HGNC	HGNC:2082. CLOCK.
HPA	HPA001867. HPA027565.
MIM	601851. gene.
neXtProt	NX_O15516.
PharmGKB	PA26609.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG14053.
HOGENOM	HBG444996.
HOVERGEN	HBG050997.
InParanoid	O15516.
OMA	GQVVQTN.
OrthoDB	EOG476JZV.
PhylomeDB	O15516.
Enzyme and pathway databases
Pathway_Interaction_DB	circadianpathway. Circadian rhythm pathway.
Reactome	REACT_24941. Circadian Clock.
Gene expression databases
ArrayExpress	O15516.
Bgee	O15516.
CleanEx	HS_CLOCK.
Genevestigator	O15516.
GermOnline	ENSG00000134852. Homo sapiens.
Family and domain databases
InterPro	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.
KO	K02223.
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]
SUPFAM	SSF47459. HLH_basic. 1 hit.
PROSITE	PS50888. HLH. 1 hit. PS50113. PAC. False negative. PS50112. PAS. 2 hits. [Graphical view]
ProtoNet	Search...
Other
NextBio	35907.
SOURCE	Search...

Entry information

Entry name

CLOCK_HUMAN

Accession

Primary (citable) accession number: O15516
Secondary accession number(s): A0AV01 , A2I2N9, O14516, Q9UIT8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	January 1, 1998
Last modified:	January 25, 2012
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.