Q5RAK8 (CLOCK_PONAB) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 78. History...
Names and origin
|Protein names||Recommended name:|
Circadian locomoter output cycles protein kaput
|Organism||Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii) [Reference proteome]|
|Taxonomic identifier||9601 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Pongo|
|Sequence length||846 AA.|
|Protein existence||Evidence at transcript level|
General annotation (Comments)
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, NR1D2, RORA, RORB and RORG, 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 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 By similarity.
Acetyl-CoA + [histone] = CoA + acetyl-[histone].
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 By similarity.
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. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with ARNTL/BMAL1 and this heterodimerization is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and ARNTL/BMAL1. Interacts with PER1, PER2 and CRY1. Interaction with PER and CRY proteins requires translocation to the nucleus. Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA. Interacts with CIPC. Interacts with NR3C1 in a ligand-dependent fashion. Interacts with RELA/p65, EIF4E, PIWIL1, DDX4 and MGEA5. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with ESR1 and estrogen stimulates this interaction. Interacts with the complex p35/CDK5. Interacts with KAT2B, CREBBP and EP300 By similarity.
Cytoplasm By similarity. Nucleus By similarity. Chromosome By similarity. Note: Localizes to sites of DNA damage in a H2AX-independent manner. 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 By similarity.
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 By similarity.
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 By similarity.
Contains 1 bHLH (basic helix-loop-helix) domain.
Contains 1 PAC (PAS-associated C-terminal) domain.
Contains 2 PAS (PER-ARNT-SIM) domains.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 846||846||Circadian locomoter output cycles protein kaput||PRO_0000262637|
|Domain||34 – 84||51||bHLH|
|Domain||107 – 177||71||PAS 1|
|Domain||262 – 332||71||PAS 2|
|Domain||336 – 379||44||PAC|
|Region||371 – 845||475||Interaction with NR3C1 By similarity|
|Region||514 – 564||51||Implicated in the circadian rhythmicity By similarity|
|Motif||32 – 47||16||Nuclear localization signal By similarity|
|Compositional bias||483 – 828||346||Gln-rich|
Amino acid modifications
|Modified residue||38||1||Phosphoserine By similarity|
|Modified residue||42||1||Phosphoserine By similarity|
|Modified residue||408||1||Phosphoserine By similarity|
|Modified residue||427||1||Phosphoserine; by GSK3-beta By similarity|
|Modified residue||451||1||Phosphothreonine; by CDK5 By similarity|
|Modified residue||461||1||Phosphothreonine; by CDK5 By similarity|
|Cross-link||67||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity|
|Cross-link||842||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity|
|CR859007 mRNA. Translation: CAH91202.1.|
|RefSeq||NP_001125706.1. NM_001132234.1. |
3D structure databases
Protocols and materials databases
Genome annotation databases
Family and domain databases
|Gene3D||4.10.280.10. 1 hit. |
|InterPro||IPR011598. bHLH_dom. |
|Pfam||PF00010. HLH. 1 hit. |
PF00989. PAS. 1 hit.
|PRINTS||PR00785. NCTRNSLOCATR. |
|SMART||SM00353. HLH. 1 hit. |
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
|SUPFAM||SSF47459. SSF47459. 1 hit. |
SSF55785. SSF55785. 2 hits.
|PROSITE||PS50888. BHLH. 1 hit. |
PS50112. PAS. 2 hits.
|Accession||Primary (citable) accession number: Q5RAK8|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families