Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0000635
UniProt IDO15516
Primary gene name(s)CLOCK
Synonym gene name(s)BHLHE8, KIAA0334
Protein nameCircadian locomoter output cycles protein kaput
Protein functionTranscriptional 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. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. 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. 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. 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. {ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24005054}.
Subcellular locationNucleus {ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:23160374}. Cytoplasm {ECO:0000250|UniProtKB:O08785}. Note=Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1-dependent. Phosphorylated form located in the nucleus while the nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2, By similarity. Localizes to sites of DNA damage in a H2AX-independent manner. {ECO:0000250|UniProtKB:O08785, ECO:0000269|PubMed:21659603}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: O15516
Gene Ontology
(Biological Process)
Complete annatation
cellular response to ionizing radiation [GO:0071479];
circadian regulation of gene expression [GO:0032922];
circadian rhythm [GO:0007623];
DNA damage checkpoint [GO:0000077];
negative regulation of glucocorticoid receptor signaling pathway [GO:2000323];
negative regulation of transcription, DNA-templated [GO:0045892];
photoperiodism [GO:0009648];
positive regulation of inflammatory response [GO:0050729];
positive regulation of NF-kappaB transcription factor activity [GO:0051092];
positive regulation of transcription, DNA-templated [GO:0045893];
positive regulation of transcription from RNA polymerase II promoter [GO:0045944];
proteasome-mediated ubiquitin-dependent protein catabolic process [GO:0043161];
regulation of hair cycle [GO:0042634];
regulation of insulin secretion [GO:0050796];
regulation of transcription, DNA-templated [GO:0006355];
regulation of transcription from RNA polymerase II promoter [GO:0006357];
regulation of type B pancreatic cell development [GO:2000074];
response to redox state [GO:0051775];
signal transduction [GO:0007165];
spermatogenesis [GO:0007283]
Gene Ontology
(Molecular Function)
Complete annatation
chromatin DNA binding [GO:0031490];
core promoter binding [GO:0001047];
core promoter sequence-specific DNA binding [GO:0001046];
DNA binding [GO:0003677];
E-box binding [GO:0070888];
histone acetyltransferase activity [GO:0004402];
RNA polymerase II core promoter proximal region sequence-specific DNA binding [GO:0000978];
sequence-specific DNA binding [GO:0043565];
transcriptional activator activity, RNA polymerase II transcription factor binding [GO:0001190];
transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding [GO:0000982];
transcription factor activity, sequence-specific DNA binding [GO:0003700]
Gene Ontology
(Cellular Component)
Complete annatation
chromatoid body [GO:0033391];
chromosome [GO:0005694];
intracellular membrane-bounded organelle [GO:0043231];
nucleoplasm [GO:0005654];
nucleus [GO:0005634];
transcription factor complex [GO:0005667]
Protein-protein interaction114944
Phylogenetic treeO15516
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD30.1836037974601790.5756676368855210.683886074181333
AZA vs. DISU0.1257789781028120.6201185486373740.960015150607793
AZA vs. IL7-0.02996518851414590.8768994860434190.999311006273513
AZA vs. SAHA-0.1510654527123160.5376035372413340.842358357086672
DISU vs. CD3-0.07034328662544980.8460892529097660.895980784026848
DISU vs. IL7-0.164384366234570.515278567524330.835160133902728
DISU vs. SAHA-0.2764785538955870.3438102031136890.721766760151331
DMSO vs. AZA-0.1119387449280360.5079728657741511
DMSO vs. CD3-0.3060078521454180.3395778431835890.453563277556589
DMSO vs. DISU-0.2394234064920020.32812839080970.829252035457872
DMSO vs. IL70.08923282294091020.6221305595596770.917463919354657
DMSO vs. SAHA-0.04700057669045750.8426273048385150.957953920413563
HIV vs. Mock in Activation0.08163660384308790.8974131652443630.999983755607037
HIV vs. Mock in Latency-0.0181941508082360.9127943909733480.999834320637052
IL7 vs. CD3-0.2047988162070130.524395281774240.651458229150809
SAHA vs. CD3-0.3604518880942030.3084061230974960.422170976026821
SAHA vs. IL7-0.1259810959068670.6063403413713610.800708280214451
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) TRUE
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.0111157 0.962895
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
unknown unknown unknown unknown unknown
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
4H10 X-ray 2.4Å B=29-89.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
HIV-1 virus replication enhanced by expression of human gene 18854154

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04710 Circadian rhythm - Homo sapiens (human)
hsa04728 Dopaminergic synapse - Homo sapiens (human)
hsa05168 Herpes simplex infection - Homo sapiens (human)