Circadian locomoter output cycles protein kaput

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Reviewed, UniProtKB/Swiss-Prot O15516 (CLOCK_HUMAN)

Last modified June 10, 2008. Version 80. History...

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Names and origin · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Circadian locomoter output cycles protein kaput
Also known as:
EC 2.3.1.48
hCLOCK

Gene names

Name:	CLOCK
Synonyms:	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 existence

Evidence at protein level.

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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.
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 By similarity.
Subcellular location	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.
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).
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.

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Ontologies

Keywords
Biological process	Biological rhythms Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator Acyltransferase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	circadian rhythm Ref.1 Traceable author statement. Source: ProtInc photoperiodism Ref.1 Traceable author statement. Source: ProtInc positive regulation of transcription from RNA polymerase II promoter Inferred from genetic interaction. Source: MGI signal transduction Ref.1 Traceable author statement. Source: ProtInc
Cellular component	transcription factor complex Inferred from physical interaction. Source: MGI
Molecular function	transcription factor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 846

846

Circadian locomoter output cycles protein kaput

Regions

Domain

48 – 85

Helix-loop-helix motif

Domain

107 – 177

PAS 1

Domain

262 – 332

PAS 2

Domain

336 – 379

PAC

DNA binding

35 – 47

Basic motif

Region

514 – 564

Implicated in the circadian rhythmicity By similarity

Compositional bias

744 – 760

Gln-rich

Compositional bias

819 – 828

Poly-Gln

Amino acid modifications

Modified residue

408

Phosphoserine By similarity

Natural variations

Natural variant

208

S → C: dbSNP rs34897046.

Natural variant

380

E → K: dbSNP rs1056478.

Natural variant

395

L → I: dbSNP rs6855837.

Natural variant

542

H → R: dbSNP rs3762836.

Experimental info

Mutagenesis

116

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

Mutagenesis

332

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

Mutagenesis

360

H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL. Some reduction of CRY1 inhibition of CLOCK-ARNTL transcriptional activity

Mutagenesis

367

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

Mutagenesis

601

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

Mutagenesis

840

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

Sequence conflict

440

S → P in AAF13733. Ref.1

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Sequences

Sequence

Length

Mass (Da)

Tools

O15516-1 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: C292B451A33E4CBF
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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

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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]	"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.
[3]	"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.
[4]	"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.
[5]	"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.

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Cross-references

Sequence databases
	AF011568 mRNA. Translation: AAB83969.1. AF097458 AF097457 Genomic DNA. Translation: AAF13733.1. AB002332 mRNA. Translation: BAA20792.2. Different initiation. BC126157 mRNA. Translation: AAI26158.1. BC126159 mRNA. Translation: AAI26160.1. AB005535 mRNA. Translation: BAA21774.1.
RefSeq	NP_004889.1.
UniGene	Hs.436975
3D structure databases
HSSP	HSSP built from PDB template 1AM9 based on UniProtKB P36956.
ModBase	Search...
PTM databases
PhosphoSite	O15516.
Genome annotation databases
Ensembl	ENSG00000134852. Homo sapiens. [Contig view]
GeneID	9575.
KEGG	hsa:9575.
Organism-specific databases
H-InvDB	HIX0004226.
HGNC	HGNC:2082. CLOCK.
HPA	HPA001867.
MIM	601851. gene.
PharmGKB	PA26609.
HUGE	Search...
GenAtlas	Search...
GeneCards	Search...
GeneLynx	Search...
Phylogenomic databases
HOGENOM	O15516.
HOVERGEN	O15516.
Gene expression databases
ArrayExpress	O15516.
CleanEx	HS_CLOCK.
GermOnline	ENSG00000134852. Homo sapiens.
Family and domain databases
InterPro	IPR001092. HLH_basic. IPR011598. HLH_DNA_bd. IPR001067. Nuc_translocat. IPR001610. PAC. IPR000014. PAS. IPR000700. PAS-assoc_C. IPR013655. PAS_3. IPR013767. PAS_fold. [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]
ProDom	O15516. [Graphical view] [Entries sharing at least one domain]
BLOCKS	Search...
Other Resources
SOURCE	Search...
ProtoNet	Search...

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Entry information

Entry name

CLOCK_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	January 1, 1998
Last modified:	June 10, 2008
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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