Circadian Clock (Homo sapiens)

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1-41226-293417, 1812, 27, 38-43338, 35-3728, 3023, 243119-2244, 4524, 2532cytosolendoplasmic reticulum lumennucleoplasmextracellular regionUbiquitinated Phosphorylated CRY ProteinsFBXL3:CRY ComplexCryptochrome-2Phosphorylated CRY ProteinsCLOCK or NPAS2Period circadian protein homolog 2NR1D1_HUMANPhosphorylated BMAL1:CLOCK/NPAS2 Heterodimer Bound to DNABMAL1:CLOCK/NPAS2 HeterodimerCasein kinase I delta or Casein kinase I epsilonCRY ProteinsCryptochrome-1DNA Containing an E-box ElementSCF-beta-TrCP1 complexPhosphorylated PER ProteinsAVPBMAL1:CLOCK/NPAS2:CRY:PER ComplexD site-binding proteinNuclear receptor ROR-alphapro-factor VII, uncarboxylatedubiquitinBeta-TrCPBMAL2:CLOCK HeterodimerBMAL1Class E basic helix-loop-helix protein 41plasminogen activator inhibitor 1CRY:PER:Kinase Ternary Complex, unphosphorylatedUbiquitinated Phosphorylated PER ProteinsCRY:PER:Kinase Ternary Complex, phosphorylatedCRY:PER:Kinase Ternary Complex, phosphorylatedNocturninubiquitinBMAL1:CLOCK/NPAS2:CRY ComplexClass E basic helix-loop-helix protein 40Glucocorticoid receptor:Dexamethasone ComplexBeta-TrCP1:PER complexFBXL3Peroxisome proliferator-activated receptor alphaPeriod circadian protein homolog 11215, 16149-1186, 7513


Description

At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning.
Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA, both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1.
BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening.
PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.
The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101648view11:51, 1 November 2018ReactomeTeamreactome version 66
101184view21:39, 31 October 2018ReactomeTeamreactome version 65
100710view20:11, 31 October 2018ReactomeTeamreactome version 64
100260view16:56, 31 October 2018ReactomeTeamreactome version 63
99813view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93971view13:48, 16 August 2017ReactomeTeamreactome version 61
93571view11:27, 9 August 2017ReactomeTeamreactome version 61
87160view19:15, 18 July 2016MkutmonOntology Term : 'regulatory pathway' added !
86673view09:23, 11 July 2016ReactomeTeamreactome version 56
83282view10:37, 18 November 2015ReactomeTeamVersion54
81401view12:55, 21 August 2015ReactomeTeamVersion53
76871view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76576view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75909view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75609view10:46, 10 June 2014ReactomeTeamReactome 48 Update
74964view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74608view08:39, 30 April 2014ReactomeTeamReactome46
42020view21:50, 4 March 2011MaintBotAutomatic update
39823view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AVP ProteinP01185 (UniProt)
BMAL1 ProteinO00327 (UniProt)
BMAL1:

CLOCK/NPAS2:CRY Complex

ComplexREACT_25684 (Reactome)
BMAL1:

CLOCK/NPAS2:CRY: PER Complex

ComplexREACT_26318 (Reactome)
BMAL1:CLOCK/NPAS2

Heterodimer

ComplexREACT_26547 (Reactome) BMAL1 (ARNTL) contains both a nuclear localization signal and a nuclear export signal. The shuttling of BMAL1 between the nucleus and cytoplasm is important for transactivation by BMAL1:CLOCK/NPAS2 and degradation of BMAL1:CLOCK/NPAS2. BMAL1 initially forms a heterodimer with CLOCK or NPAS2 in the cytosol. The heterodimer is then phosphorylated and translocated into the nucleus.
BMAL2:CLOCK

Heterodimer

ComplexREACT_26482 (Reactome)
Beta-TrCP ProteinQ9Y297 (UniProt)
Beta-TrCP1:PER

complex

ComplexREACT_27062 (Reactome)
CLOCK or

NPAS2

ProteinREACT_26942 (Reactome)
CRY Proteins ProteinREACT_26101 (Reactome)
CRY:PER:Kinase

Ternary Complex, phosphorylated

ComplexREACT_25528 (Reactome)
CRY:PER:Kinase

Ternary Complex, phosphorylated

ComplexREACT_26285 (Reactome)
CRY:PER:Kinase

Ternary Complex, unphosphorylated

ComplexREACT_26725 (Reactome) As inferred from mouse, PER proteins can form homodimers and CRY proteins can form heterodimers with PER proteins. CRY and PER proteins may therefore form trimers (PER:PER:CRY).
Casein kinase I delta

or Casein kinase I epsilon

UnknownREACT_26408 (Reactome)
Class E basic helix-

loop-helix protein 40

ProteinO14503 (UniProt)
Class E basic helix-

loop-helix protein 41

ProteinQ9C0J9 (UniProt)
Cryptochrome-

1

ProteinQ16526 (UniProt)
Cryptochrome-

2

ProteinQ49AN0 (UniProt)
D site-binding

protein

ProteinQ10586 (UniProt)
DNA Containing an

E-box Element

UnknownREACT_25457 (Reactome) The consensus sequence of the E-box is CACGTG.
FBXL3 ProteinQ9UKT7 (UniProt)
FBXL3:CRY

Complex

ComplexREACT_25657 (Reactome)
Glucocorticoid

receptor: Dexamethasone Complex

ComplexREACT_26089 (Reactome)
NR1D1_HUMAN ProteinP20393 (UniProt)
Nocturnin ProteinQ9UK39 (UniProt)
Nuclear receptor

ROR-alpha

ProteinP35398 (UniProt)
Period circadian

protein homolog 1

ProteinO15534 (UniProt)
Period circadian

protein homolog 2

ProteinO15055 (UniProt)
Peroxisome

proliferator-activated receptor alpha

ProteinQ07869 (UniProt)
Phosphorylated

BMAL1:CLOCK/NPAS2 Heterodimer Bound to DNA

ComplexREACT_25790 (Reactome)
Phosphorylated

PER Proteins

ProteinREACT_25419 (Reactome)
Phosphorylated CRY

Proteins

ProteinREACT_26910 (Reactome)
SCF-beta-TrCP1

complex

ComplexREACT_6992 (Reactome)
Ubiquitinated

Phosphorylated PER Proteins

ProteinREACT_25524 (Reactome)
Ubiquitinated

Phosphorylated CRY Proteins

ProteinREACT_26499 (Reactome)
plasminogen activator

inhibitor 1

ProteinP05121 (UniProt)
pro-factor VII,

uncarboxylated

ProteinP08709 (UniProt)
ubiquitin ProteinREACT_3316 (Reactome)
ubiquitin ProteinREACT_3995 (Reactome)

Annotated Interactions

No annotated interactions

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