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Entry version 199 (13 Nov 2019)
Sequence version 1 (01 Jan 1998)
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Protein

Circadian locomoter output cycles protein kaput

Gene

CLOCK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity).By similarity9 Publications

Miscellaneous

CLOCK-ARNTL/BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-ARNTL/BMAl1 transcriptional activity of PER1 and disrupt circadian rhythmicity.

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity regulationi

There is conflicting data about the effect of NAD cofactors on activity. PubMed:11441146 suggests that the redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer. PubMed:23229515 reports that NADH and NADPH have no significant effect on DNA-binding activity of the CLOCK-ARNTL/BMAL1 heterodimer.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei84Important for interaction with ARNTL/BMAL11 Publication1

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionActivator, Acyltransferase, DNA-binding, Transferase
Biological processBiological rhythms, DNA damage, Transcription, Transcription regulation

Enzyme and pathway databases

Reactome - a knowledgebase of biological pathways and processes

More...
Reactomei
R-HSA-1368108 BMAL1:CLOCK,NPAS2 activates circadian gene expression
R-HSA-1989781 PPARA activates gene expression
R-HSA-3214847 HATs acetylate histones
R-HSA-400253 Circadian Clock

SIGNOR Signaling Network Open Resource

More...
SIGNORi
O15516

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Circadian locomoter output cycles protein kaput (EC:2.3.1.48)
Short name:
hCLOCK
Alternative name(s):
Class E basic helix-loop-helix protein 8
Short name:
bHLHe8
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:CLOCK
Synonyms:BHLHE8, KIAA0334
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 4

Organism-specific databases

Human Gene Nomenclature Database

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HGNCi
HGNC:2082 CLOCK

Online Mendelian Inheritance in Man (OMIM)

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MIMi
601851 gene

neXtProt; the human protein knowledge platform

More...
neXtProti
NX_O15516

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi38S → E: Phosphomimetic mutant with no effect on DNA binding or CLOCK-ARNTL/BMAL1 transcriptional activity. 1 Publication1
Mutagenesisi42S → E: Phosphomimetic mutant with no effect on DNA binding or CLOCK-ARNTL/BMAL1 transcriptional activity. 1 Publication1
Mutagenesisi50F → M: No effect on ARNTL/BMAL1 binding. 1 Publication1
Mutagenesisi84H → L: Impaired ARNTL/BMAL1 binding. 1 Publication1
Mutagenesisi116E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with K-367 and L-601. 1 Publication1
Mutagenesisi332G → E: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with L-840. 1 Publication1
Mutagenesisi360H → Y: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity. 1 Publication1
Mutagenesisi367E → K: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with E-116 and L-601. 1 Publication1
Mutagenesisi451T → F: Significant loss in phosphorylation. 1 Publication1
Mutagenesisi461T → F: Significant loss in phosphorylation. 1 Publication1
Mutagenesisi601V → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with K-116 and K-367. 1 Publication1
Mutagenesisi840P → L: 3-fold increase in PER1 reporter activity by CLOCK-ARNTL/BMAL1. Some reduction of CRY1 inhibition of CLOCK-ARNTL/BMAL1 transcriptional activity; when associated with E-332. 1 Publication1

Organism-specific databases

DisGeNET

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DisGeNETi
9575

Open Targets

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OpenTargetsi
ENSG00000134852

The Pharmacogenetics and Pharmacogenomics Knowledge Base

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PharmGKBi
PA26609

Miscellaneous databases

Pharos NIH Druggable Genome Knowledgebase

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Pharosi
O15516

Polymorphism and mutation databases

BioMuta curated single-nucleotide variation and disease association database

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BioMutai
CLOCK

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_00001271631 – 846Circadian locomoter output cycles protein kaputAdd BLAST846

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei38PhosphoserineBy similarity1
Modified residuei42PhosphoserineBy similarity1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section describes <strong>covalent linkages</strong> of various types formed <strong>between two proteins (interchain cross-links)</strong> or <strong>between two parts of the same protein (intrachain cross-links)</strong>, except the disulfide bonds that are annotated in the <a href="http://www.uniprot.org/manual/disulfid">'Disulfide bond'</a> subsection.<p><a href='/help/crosslnk' target='_top'>More...</a></p>Cross-linki67Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity
Modified residuei408PhosphoserineBy similarity1
Modified residuei427Phosphoserine; by GSK3-betaBy similarity1
Modified residuei431PhosphoserineBy similarity1
Modified residuei451Phosphothreonine; by CDK51 Publication1
Modified residuei461Phosphothreonine; by CDK51 Publication1
Cross-linki842Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi

Ubiquitinated, leading to its proteasomal degradation.By similarity
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2.By similarity
Phosphorylation is dependent on the CLOCK-ARNTL/BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver. May be phosphorylated by CSNK1D and CKSN1E.1 Publication
Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity. Sumoylation stimulates cell proliferation and increases the proportion of S phase cells in breast cancer cell lines.1 Publication
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

Encyclopedia of Proteome Dynamics

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EPDi
O15516

jPOST - Japan Proteome Standard Repository/Database

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jPOSTi
O15516

MassIVE - Mass Spectrometry Interactive Virtual Environment

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MassIVEi
O15516

MaxQB - The MaxQuant DataBase

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MaxQBi
O15516

PaxDb, a database of protein abundance averages across all three domains of life

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PaxDbi
O15516

PeptideAtlas

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PeptideAtlasi
O15516

PRoteomics IDEntifications database

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PRIDEi
O15516

ProteomicsDB: a multi-organism proteome resource

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ProteomicsDBi
48706

PTM databases

iPTMnet integrated resource for PTMs in systems biology context

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iPTMneti
O15516

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

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PhosphoSitePlusi
O15516

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

<p>This subsection of the ‘Expression’ section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms. By default, the information is derived from experiments at the mRNA level, unless specified ‘at protein level’. <br></br>Examples: <a href="http://www.uniprot.org/uniprot/P92958#expression">P92958</a>, <a href="http://www.uniprot.org/uniprot/Q8TDN4#expression">Q8TDN4</a>, <a href="http://www.uniprot.org/uniprot/O14734#expression">O14734</a><p><a href='/help/tissue_specificity' target='_top'>More...</a></p>Tissue specificityi

Hair follicles (at protein level). 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).2 Publications

Gene expression databases

Bgee dataBase for Gene Expression Evolution

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Bgeei
ENSG00000134852 Expressed in 237 organ(s), highest expression level in secondary oocyte

ExpressionAtlas, Differential and Baseline Expression

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ExpressionAtlasi
O15516 baseline and differential

Genevisible search portal to normalized and curated expression data from Genevestigator

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Genevisiblei
O15516 HS

Organism-specific databases

Human Protein Atlas

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HPAi
HPA001867
HPA027565

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction_section">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>Subunit structurei

Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity).

Interacts with KMT2A; in a circadian manner (By similarity).

Forms a heterodimer with ARNTL/BMAL1 (PubMed:21613214, PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and ARNTL/BMAL1 (By similarity).

Interacts with NR3C1 in a ligand-dependent fashion (PubMed:21980503).

Interacts with ESR1 and estrogen stimulates this interaction (PubMed:23160374).

Interacts with the complex p35/CDK5 (PubMed:24235147).

Interacts with RELA/p65 (By similarity).

Interacts with KAT2B, CREBBP, EP300 (PubMed:14645221).

Interacts with ID1 and ID3 (By similarity).

Interacts with ID2 (PubMed:20861012).

Interacts with MTA1 (By similarity).

Interacts with OGA (By similarity).

Interacts with SIRT1 (By similarity).

Interacts with CIPC (By similarity).

Interacts with EZH2 (By similarity).

Interacts with EIF4E, PIWIL1 and DDX4 (By similarity).

Interacts with PER2 and CRY1 and the interaction with PER and CRY proteins requires translocation to the nucleus.

Interacts with PER1 and CRY2 (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation (PubMed:21613214). Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (PubMed:21613214). The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B.

Interacts with KDM5A (PubMed:21960634).

Interacts with MYBBP1A (By similarity).

Interacts with THRAP3 (By similarity).

Interacts with MED1; this interaction requires the presence of THRAP3 (By similarity).

Interacts with NCOA2 (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1 (PubMed:25936801).

Interacts with ASS1 and IMPDH2; in a circadian manner (PubMed:28985504).

Interacts with NDUFA9 (PubMed:28985504).

Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391).

Interacts with HNF4A (PubMed:30530698).

By similarity12 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei39Interaction with E-box DNA1 Publication1
Sitei43Interaction with E-box DNA1 Publication1
Sitei47Interaction with E-box DNA1 Publication1

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction_section%27">Interaction</a> section provides information about binary protein-protein interactions. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the <a href="http://www.ebi.ac.uk/intact/">IntAct database</a>. It is updated on a monthly basis. Each binary interaction is displayed on a separate line.<p><a href='/help/binary_interactions' target='_top'>More...</a></p>Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

The Biological General Repository for Interaction Datasets (BioGrid)

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BioGridi
114944, 66 interactors

ComplexPortal: manually curated resource of macromolecular complexes

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ComplexPortali
CPX-3229 CLOCK-BMAL1 transcription complex
CPX-3230 CLOCK-BMAL2 transcription complex

CORUM comprehensive resource of mammalian protein complexes

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CORUMi
O15516

Database of interacting proteins

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DIPi
DIP-46009N

Protein interaction database and analysis system

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IntActi
O15516, 14 interactors

STRING: functional protein association networks

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STRINGi
9606.ENSP00000308741

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

1846
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

SWISS-MODEL Repository - a database of annotated 3D protein structure models

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SMRi
O15516

Database of comparative protein structure models

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ModBasei
Search...

Protein Data Bank in Europe - Knowledge Base

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PDBe-KBi
Search...

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/family_and_domains_section">Family and Domains</a> section describes the position and type of a domain, which is defined as a specific combination of secondary structures organized into a characteristic three-dimensional structure or fold.<p><a href='/help/domain' target='_top'>More...</a></p>Domaini34 – 84bHLHPROSITE-ProRule annotationAdd BLAST51
Domaini107 – 177PAS 1PROSITE-ProRule annotationAdd BLAST71
Domaini262 – 332PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini336 – 379PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes a region of interest that cannot be described in other subsections.<p><a href='/help/region' target='_top'>More...</a></p>Regioni371 – 845Interaction with NR3C1By similarityAdd BLAST475
Regioni450 – 570Interaction with SIRT1By similarityAdd BLAST121
Regioni514 – 564Implicated in the circadian rhythmicityBy similarityAdd BLAST51

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes a short (usually not more than 20 amino acids) conserved sequence motif of biological significance.<p><a href='/help/motif' target='_top'>More...</a></p>Motifi32 – 47Nuclear localization signalBy similarityAdd BLAST16

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes the position of regions of compositional bias within the protein and the particular amino acids that are over-represented within those regions.<p><a href='/help/compbias' target='_top'>More...</a></p>Compositional biasi744 – 760Gln-richAdd BLAST17
Compositional biasi819 – 828Poly-Gln10

Keywords - Domaini

Repeat

Phylogenomic databases

evolutionary genealogy of genes: Non-supervised Orthologous Groups

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eggNOGi
ENOG410IQ5V Eukaryota
ENOG410Y7Z8 LUCA

Ensembl GeneTree

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GeneTreei
ENSGT00940000157580

The HOGENOM Database of Homologous Genes from Fully Sequenced Organisms

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HOGENOMi
HOG000234382

InParanoid: Eukaryotic Ortholog Groups

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InParanoidi
O15516

KEGG Orthology (KO)

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KOi
K02223

Identification of Orthologs from Complete Genome Data

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OMAi
DNLAKCH

Database of Orthologous Groups

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OrthoDBi
205871at2759

Database for complete collections of gene phylogenies

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PhylomeDBi
O15516

TreeFam database of animal gene trees

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TreeFami
TF324568

Family and domain databases

Conserved Domains Database

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CDDi
cd00083 HLH, 1 hit
cd00130 PAS, 2 hits

Gene3D Structural and Functional Annotation of Protein Families

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Gene3Di
4.10.280.10, 1 hit

Integrated resource of protein families, domains and functional sites

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InterProi
View protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold

Pfam protein domain database

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Pfami
View protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit

Protein Motif fingerprint database; a protein domain database

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PRINTSi
PR00785 NCTRNSLOCATR

Simple Modular Architecture Research Tool; a protein domain database

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SMARTi
View protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits

Superfamily database of structural and functional annotation

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SUPFAMi
SSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits

PROSITE; a protein domain and family database

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PROSITEi
View protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

<p>This section displays by default the canonical protein sequence and upon request all isoforms described in the entry. It also includes information pertinent to the sequence(s), including <a href="http://www.uniprot.org/help/sequence_length">length</a> and <a href="http://www.uniprot.org/help/sequences">molecular weight</a>. The information is filed in different subsections. The current subsections and their content are listed below:<p><a href='/help/sequences_section' target='_top'>More...</a></p>Sequence (1+)i

<p>This subsection of the <a href="http://www.uniprot.org/help/sequences_section">Sequence</a> section indicates if the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> displayed by default in the entry is complete or not.<p><a href='/help/sequence_status' target='_top'>More...</a></p>Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

O15516-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF
60 70 80 90 100
NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW
110 120 130 140 150
KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV
160 170 180 190 200
DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG
210 220 230 240 250
TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT HRPSYEDRVC
260 270 280 290 300
FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL
310 320 330 340 350
PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW
360 370 380 390 400
LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA
410 420 430 440 450
DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS
460 470 480 490 500
TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS
510 520 530 540 550
QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK
560 570 580 590 600
IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ
610 620 630 640 650
VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP
660 670 680 690 700
SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ
710 720 730 740 750
IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT
760 770 780 790 800
LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL
810 820 830 840
ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ
Length:846
Mass (Da):95,304
Last modified:January 1, 1998 - v1
<p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.</p> <p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.</p> <p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).</p> <p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x<sup>64</sup> + x<sup>4</sup> + x<sup>3</sup> + x + 1. The algorithm is described in the ISO 3309 standard. </p> <p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.<br /> <strong>Cyclic redundancy and other checksums</strong><br /> <a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993)</a>)</p> Checksum:iC292B451A33E4CBF
GO

<p>In eukaryotic reference proteomes, unreviewed entries that are likely to belong to the same gene are computationally mapped, based on gene identifiers from Ensembl, EnsemblGenomes and model organism databases.<p><a href='/help/gene_centric_isoform_mapping' target='_top'>More...</a></p>Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
C9JK03C9JK03_HUMAN
Circadian locomoter output cycles p...
CLOCK
182Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>

<p>This subsection of the ‘Sequence’ section reports difference(s) between the protein sequence shown in the UniProtKB entry and other available protein sequences derived from the same gene.<p><a href='/help/sequence_caution' target='_top'>More...</a></p>Sequence cautioni

The sequence BAA20792 differs from that shown. Reason: Erroneous initiation. Extended N-terminus.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section reports difference(s) between the canonical sequence (displayed by default in the entry) and the different sequence submissions merged in the entry. These various submissions may originate from different sequencing projects, different types of experiments, or different biological samples. Sequence conflicts are usually of unknown origin.<p><a href='/help/conflict' target='_top'>More...</a></p>Sequence conflicti440S → P in AAF13733 (PubMed:10198158).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_040061208S → C. Corresponds to variant dbSNP:rs34897046Ensembl.1
Natural variantiVAR_040062380E → K. Corresponds to variant dbSNP:rs1056478Ensembl.1
Natural variantiVAR_029076395L → I. Corresponds to variant dbSNP:rs6855837Ensembl.1
Natural variantiVAR_029077542H → R. Corresponds to variant dbSNP:rs3762836Ensembl.1

Sequence databases

Select the link destinations:

EMBL nucleotide sequence database

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EMBLi

GenBank nucleotide sequence database

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GenBanki

DNA Data Bank of Japan; a nucleotide sequence database

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DDBJi
Links Updated
AF011568 mRNA Translation: AAB83969.1
AH008440 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

The Consensus CDS (CCDS) project

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CCDSi
CCDS3500.1

NCBI Reference Sequences

More...
RefSeqi
NP_001254772.1, NM_001267843.1
NP_004889.1, NM_004898.3
XP_005265844.1, XM_005265787.2
XP_011532711.1, XM_011534409.2
XP_011532712.1, XM_011534410.2
XP_011532713.1, XM_011534411.2
XP_016864343.1, XM_017008854.1

Genome annotation databases

Ensembl eukaryotic genome annotation project

More...
Ensembli
ENST00000309964; ENSP00000308741; ENSG00000134852
ENST00000381322; ENSP00000370723; ENSG00000134852
ENST00000513440; ENSP00000426983; ENSG00000134852

Database of genes from NCBI RefSeq genomes

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GeneIDi
9575

KEGG: Kyoto Encyclopedia of Genes and Genomes

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KEGGi
hsa:9575

UCSC genome browser

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UCSCi
uc003haz.3 human

Keywords - Coding sequence diversityi

Polymorphism

<p>This section provides links to proteins that are similar to the protein sequence(s) described in this entry at different levels of sequence identity thresholds (100%, 90% and 50%) based on their membership in UniProt Reference Clusters (<a href="http://www.uniprot.org/help/uniref">UniRef</a>).<p><a href='/help/similar_proteins_section' target='_top'>More...</a></p>Similar proteinsi

<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF011568 mRNA Translation: AAB83969.1
AH008440 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
CCDSiCCDS3500.1
RefSeqiNP_001254772.1, NM_001267843.1
NP_004889.1, NM_004898.3
XP_005265844.1, XM_005265787.2
XP_011532711.1, XM_011534409.2
XP_011532712.1, XM_011534410.2
XP_011532713.1, XM_011534411.2
XP_016864343.1, XM_017008854.1

3D structure databases

Select the link destinations:

Protein Data Bank Europe

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PDBei

Protein Data Bank RCSB

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RCSB PDBi

Protein Data Bank Japan

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PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4H10X-ray2.40B29-89[»]
6QPJX-ray2.31A105-265[»]
SMRiO15516
ModBaseiSearch...
PDBe-KBiSearch...

Protein-protein interaction databases

BioGridi114944, 66 interactors
ComplexPortaliCPX-3229 CLOCK-BMAL1 transcription complex
CPX-3230 CLOCK-BMAL2 transcription complex
CORUMiO15516
DIPiDIP-46009N
IntActiO15516, 14 interactors
STRINGi9606.ENSP00000308741

PTM databases

iPTMnetiO15516
PhosphoSitePlusiO15516

Polymorphism and mutation databases

BioMutaiCLOCK

Proteomic databases

EPDiO15516
jPOSTiO15516
MassIVEiO15516
MaxQBiO15516
PaxDbiO15516
PeptideAtlasiO15516
PRIDEiO15516
ProteomicsDBi48706

Protocols and materials databases

The DNASU plasmid repository

More...
DNASUi
9575

Genome annotation databases

EnsembliENST00000309964; ENSP00000308741; ENSG00000134852
ENST00000381322; ENSP00000370723; ENSG00000134852
ENST00000513440; ENSP00000426983; ENSG00000134852
GeneIDi9575
KEGGihsa:9575
UCSCiuc003haz.3 human

Organism-specific databases

Comparative Toxicogenomics Database

More...
CTDi
9575
DisGeNETi9575

GeneCards: human genes, protein and diseases

More...
GeneCardsi
CLOCK
HGNCiHGNC:2082 CLOCK
HPAiHPA001867
HPA027565
MIMi601851 gene
neXtProtiNX_O15516
OpenTargetsiENSG00000134852
PharmGKBiPA26609

Human Unidentified Gene-Encoded large proteins database

More...
HUGEi
Search...

GenAtlas: human gene database

More...
GenAtlasi
Search...

Phylogenomic databases

eggNOGiENOG410IQ5V Eukaryota
ENOG410Y7Z8 LUCA
GeneTreeiENSGT00940000157580
HOGENOMiHOG000234382
InParanoidiO15516
KOiK02223
OMAiDNLAKCH
OrthoDBi205871at2759
PhylomeDBiO15516
TreeFamiTF324568

Enzyme and pathway databases

ReactomeiR-HSA-1368108 BMAL1:CLOCK,NPAS2 activates circadian gene expression
R-HSA-1989781 PPARA activates gene expression
R-HSA-3214847 HATs acetylate histones
R-HSA-400253 Circadian Clock
SIGNORiO15516

Miscellaneous databases

ChiTaRS: a database of human, mouse and fruit fly chimeric transcripts and RNA-sequencing data

More...
ChiTaRSi
CLOCK human

The Gene Wiki collection of pages on human genes and proteins

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GeneWikii
CLOCK

Database of phenotypes from RNA interference screens in Drosophila and Homo sapiens

More...
GenomeRNAii
9575
PharosiO15516

Protein Ontology

More...
PROi
PR:O15516

The Stanford Online Universal Resource for Clones and ESTs

More...
SOURCEi
Search...

Gene expression databases

BgeeiENSG00000134852 Expressed in 237 organ(s), highest expression level in secondary oocyte
ExpressionAtlasiO15516 baseline and differential
GenevisibleiO15516 HS

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

ProtoNet; Automatic hierarchical classification of proteins

More...
ProtoNeti
Search...

MobiDB: a database of protein disorder and mobility annotations

More...
MobiDBi
Search...

<p>This section provides general information on the entry.<p><a href='/help/entry_information_section' target='_top'>More...</a></p>Entry informationi

<p>This subsection of the ‘Entry information’ section provides a mnemonic identifier for a UniProtKB entry, but it is not a stable identifier. Each reviewed entry is assigned a unique entry name upon integration into UniProtKB/Swiss-Prot.<p><a href='/help/entry_name' target='_top'>More...</a></p>Entry nameiCLOCK_HUMAN
<p>This subsection of the ‘Entry information’ section provides one or more accession number(s). These are stable identifiers and should be used to cite UniProtKB entries. Upon integration into UniProtKB, each entry is assigned a unique accession number, which is called ‘Primary (citable) accession number’.<p><a href='/help/accession_numbers' target='_top'>More...</a></p>AccessioniPrimary (citable) accession number: O15516
Secondary accession number(s): A0AV01
, A2I2N9, O14516, Q9UIT8
<p>This subsection of the ‘Entry information’ section shows the date of integration of the entry into UniProtKB, the date of the last sequence update and the date of the last annotation modification (‘Last modified’). The version number for both the entry and the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> are also displayed.<p><a href='/help/entry_history' target='_top'>More...</a></p>Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 1, 1998
Last modified: November 13, 2019
This is version 199 of the entry and version 1 of the sequence. See complete history.
<p>This subsection of the ‘Entry information’ section indicates whether the entry has been manually annotated and reviewed by UniProtKB curators or not, in other words, if the entry belongs to the Swiss-Prot section of UniProtKB (<strong>reviewed</strong>) or to the computer-annotated TrEMBL section (<strong>unreviewed</strong>).<p><a href='/help/entry_status' target='_top'>More...</a></p>Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

<p>This section contains any relevant information that doesn’t fit in any other defined sections<p><a href='/help/miscellaneous_section' target='_top'>More...</a></p>Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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