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P97460

- NPAS2_MOUSE

UniProt

P97460 - NPAS2_MOUSE

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Protein

Neuronal PAS domain-containing protein 2

Gene

Npas2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

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. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes.10 Publications

Cofactori

Binds heme.2 Publications

Enzyme regulationi

Carbon monoxide (CO) and the redox state of the cell can modulate the transcriptional activity of the NPAS2-ARNTL/BMAL1 heterodimer. NADH and NADPH enhance the DNA-binding activity of the heterodimer whereas CO binds the heme group in NPAS2 and inhibits the DNA-binding activity of the heterodimer.2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi119 – 1191Iron (heme B axial ligand)2 Publications
Metal bindingi171 – 1711Iron (heme B axial ligand)2 Publications

GO - Molecular functioni

  1. core promoter binding Source: UniProtKB
  2. DNA binding Source: UniProtKB
  3. metal ion binding Source: UniProtKB-KW
  4. sequence-specific DNA binding transcription factor activity Source: InterPro
  5. signal transducer activity Source: InterPro

GO - Biological processi

  1. cellular response to DNA damage stimulus Source: UniProtKB-KW
  2. circadian regulation of gene expression Source: UniProtKB
  3. circadian rhythm Source: UniProtKB
  4. circadian sleep/wake cycle Source: MGI
  5. locomotor rhythm Source: MGI
  6. negative regulation of cell death Source: UniProtKB
  7. positive regulation of DNA repair Source: UniProtKB
  8. positive regulation of transcription, DNA-templated Source: UniProtKB
  9. regulation of circadian rhythm Source: UniProtKB
  10. regulation of response to DNA damage stimulus Source: UniProtKB
  11. response to redox state Source: UniProtKB
  12. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Biological rhythms, DNA damage, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Heme, Iron, Metal-binding

Enzyme and pathway databases

ReactomeiREACT_115781. Bmal1:Clock,Npas2 activates circadian gene expression.
REACT_198351. RORA activates circadian gene expression.
REACT_198602. PPARA activates gene expression.
REACT_198620. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
REACT_24972. Circadian Clock.

Names & Taxonomyi

Protein namesi
Recommended name:
Neuronal PAS domain-containing protein 2
Short name:
Neuronal PAS2
Gene namesi
Name:Npas2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Unplaced

Organism-specific databases

MGIiMGI:109232. Npas2.

Subcellular locationi

Nucleus 1 PublicationPROSITE-ProRule annotation

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. nucleoplasm Source: Reactome
  3. nucleus Source: UniProtKB
  4. transcription factor complex Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice exhibit altered sleep and locomotor activity. Show alterations in sleep homeostasis, altering the electrophysiological properties of neurons after sleep deprivation. Display normal patterns of sleep throughout the light period, however during the active, nocturnal period, they remain awake nearly continuously for the first 8 to 9 hours of darkness and tend to fast rather than readapt to eating in daylight. Exhibit a dysregualtion in the lipid and fatty acid metabolism pathways and a significant reduction in daytime contrast sensitivity.5 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi119 – 1191H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. 1 Publication
Mutagenesisi171 – 1711H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 816816Neuronal PAS domain-containing protein 2PRO_0000127407Add
BLAST

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiP97460.
PRIDEiP97460.

PTM databases

PhosphoSiteiP97460.

Expressioni

Tissue specificityi

Expressed in the retinal ganglion cells (at protein level). Expressed in the hypothalamic suprachiasmatic CC nuclei (SCN) of the brain. Also found in spinal cord, and to a lesser extent in colon, small intestine and uterus.3 Publications

Developmental stagei

First detected 3 days after birth.1 Publication

Inductioni

Expression in the retinal ganglion cells and heart oscillates in a circadian manner.2 Publications

Gene expression databases

CleanExiMM_NPAS2.
GenevestigatoriP97460.

Interactioni

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. Efficient DNA binding requires dimerization with another bHLH protein. Interacts with NCOA3, KAT2B and CREBBP By similarity. Forms a heterodimer with ARNTL/BMAL1 and this heterodimerization is required for E-box-dependent transactivation. Interacts with EP300.By similarity2 Publications

Protein-protein interaction databases

IntActiP97460. 1 interaction.

Structurei

3D structure databases

ProteinModelPortaliP97460.
SMRiP97460. Positions 6-359.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini9 – 5951bHLHPROSITE-ProRule annotationAdd
BLAST
Domaini82 – 15271PAS 1PROSITE-ProRule annotationAdd
BLAST
Domaini237 – 30771PAS 2PROSITE-ProRule annotationAdd
BLAST
Domaini311 – 35444PACAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 6161Sufficient for heterodimer formation with ARNTL/BMAL1, E-box binding and for the effect of NADPH1 PublicationAdd
BLAST

Sequence similaritiesi

Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiNOG300360.
HOGENOMiHOG000234382.
HOVERGENiHBG050997.
InParanoidiP97460.
KOiK09026.
PhylomeDBiP97460.

Family and domain databases

Gene3Di4.10.280.10. 1 hit.
InterProiIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamiPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSiPR00785. NCTRNSLOCATR.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsiTIGR00229. sensory_box. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P97460-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MDEDEKDRAK RASRNKSEKK RRDQFNVLIK ELSSMLPGNT RKMDKTTVLE
60 70 80 90 100
KVIGFLQKHN EVSAQTEICD IQQDWKPSFL SNEEFTQLML EALDGFVIVV
110 120 130 140 150
TTDGSIIYVS DSITPLLGHL PADVMDQNLL NFLPEQEHSE VYKILSSHML
160 170 180 190 200
VTDSPSPEFL KSDNDLEFYC HLLRGSLNPK EFPTYEYIKF VGNFRSYNNV
210 220 230 240 250
PSPSCNGFDN TLSRPCHVPL GKDVCFIATV RLATPQFLKE MCVADEPLEE
260 270 280 290 300
FTSRHSLEWK FLFLDHRAPP IIGYLPFEVL GTSGYNYYHI DDLELLARCH
310 320 330 340 350
QHLMQFGKGK SCCYRFLTKG QQWIWLQTHY YITYHQWNSK PEFIVCTHSV
360 370 380 390 400
VSYADVRVER RQELALEDPP TEAMHPSAVK EKDSSLEPPQ PFNALDMGAS
410 420 430 440 450
GLPSSPSPSA SSRSSHKSSH TAMSEPTSTP TKLMAENSTT ALPRPATLPQ
460 470 480 490 500
ELPVQGLSQA ATMPTALHSS ASCDLTKQLL LQSLPQTGLQ SPPAPVTQFS
510 520 530 540 550
AQFSMFQTIK DQLEQRTRIL QANIRWQQEE LHKIQEQLCL VQDSNVQMFL
560 570 580 590 600
QQPAVSLSFS STQRPAAQQQ LQQRPAAPSQ PQLVVNTPLQ GQITSTQVTN
610 620 630 640 650
QHLLRESNVI SAQGPKPMRS SQLLPASGRS LSSLPSQFSS TASVLPPGLS
660 670 680 690 700
LTTIAPTPQD DSQCQPSPDF GHDRQLRLLL SQPIQPMMPG SCDARQPSEV
710 720 730 740 750
SRTGRQVKYA QSQVMFPSPD SHPTNSSAST PVLLMGQAVL HPSFPASRPS
760 770 780 790 800
PLQPAQAQQQ PPPYLQAPTS LHSEQPDSLL LSTFSQQPGT LGYAATQSTP
810
PQPPRPSRRV SRLSES
Length:816
Mass (Da):90,916
Last modified:May 1, 1997 - v1
Checksum:i7E5CF0641CFDC1DD
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U77969 mRNA. Translation: AAB47249.1.
CCDSiCCDS48244.1.
RefSeqiNP_032745.2. NM_008719.2.
UniGeneiMm.2380.

Genome annotation databases

GeneIDi18143.
KEGGimmu:18143.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U77969 mRNA. Translation: AAB47249.1 .
CCDSi CCDS48244.1.
RefSeqi NP_032745.2. NM_008719.2.
UniGenei Mm.2380.

3D structure databases

ProteinModelPortali P97460.
SMRi P97460. Positions 6-359.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

IntActi P97460. 1 interaction.

PTM databases

PhosphoSitei P97460.

Proteomic databases

PaxDbi P97460.
PRIDEi P97460.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 18143.
KEGGi mmu:18143.

Organism-specific databases

CTDi 4862.
MGIi MGI:109232. Npas2.

Phylogenomic databases

eggNOGi NOG300360.
HOGENOMi HOG000234382.
HOVERGENi HBG050997.
InParanoidi P97460.
KOi K09026.
PhylomeDBi P97460.

Enzyme and pathway databases

Reactomei REACT_115781. Bmal1:Clock,Npas2 activates circadian gene expression.
REACT_198351. RORA activates circadian gene expression.
REACT_198602. PPARA activates gene expression.
REACT_198620. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
REACT_24972. Circadian Clock.

Miscellaneous databases

NextBioi 293396.
PROi P97460.
SOURCEi Search...

Gene expression databases

CleanExi MM_NPAS2.
Genevestigatori P97460.

Family and domain databases

Gene3Di 4.10.280.10. 1 hit.
InterProi IPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view ]
Pfami PF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view ]
PRINTSi PR00785. NCTRNSLOCATR.
SMARTi SM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view ]
SUPFAMi SSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsi TIGR00229. sensory_box. 1 hit.
PROSITEi PS50888. BHLH. 1 hit.
PS50112. PAS. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system."
    Zhou Y.-D., Barnard M., Tian H., Li X., Ring H.Z., Francke U., Shelton J., Richardson J., Russell D.W., McKnight S.L.
    Proc. Natl. Acad. Sci. U.S.A. 94:713-718(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE, TISSUE SPECIFICITY.
    Tissue: Brain.
  2. "Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice."
    Dudley C.A., Erbel-Sieler C., Estill S.J., Reick M., Franken P., Pitts S., McKnight S.L.
    Science 301:379-383(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  3. "Histone acetyltransferase-dependent chromatin remodeling and the vascular clock."
    Curtis A.M., Seo S.B., Westgate E.J., Rudic R.D., Smyth E.M., Chakravarti D., FitzGerald G.A., McNamara P.
    J. Biol. Chem. 279:7091-7097(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EP300, INDUCTION.
  4. "CO-dependent activity-controlling mechanism of heme-containing CO-sensor protein, neuronal PAS domain protein 2."
    Uchida T., Sato E., Sato A., Sagami I., Shimizu T., Kitagawa T.
    J. Biol. Chem. 280:21358-21368(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: HEME-BINDING, RESONANCE RAMAN SPECTROSCOPY, ENZYME REGULATION.
  5. "Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES."
    Kondratov R.V., Kondratova A.A., Lee C., Gorbacheva V.Y., Chernov M.V., Antoch M.P.
    Cell Cycle 5:890-895(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ARNTL/BMAL1, FUNCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION.
  6. "NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions."
    Franken P., Dudley C.A., Estill S.J., Barakat M., Thomason R., O'Hara B.F., McKnight S.L.
    Proc. Natl. Acad. Sci. U.S.A. 103:7118-7123(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  7. "CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock."
    DeBruyne J.P., Weaver D.R., Reppert S.M.
    Nat. Neurosci. 10:543-545(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
  8. "Effects of mutations in the heme domain on the transcriptional activity and DNA-binding activity of NPAS2."
    Ishida M., Ueha T., Sagami I.
    Biochem. Biophys. Res. Commun. 368:292-297(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DNA-BINDING, MUTAGENESIS OF HIS-119 AND HIS-171.
  9. "Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood."
    Hampp G., Ripperger J.A., Houben T., Schmutz I., Blex C., Perreau-Lenz S., Brunk I., Spanagel R., Ahnert-Hilger G., Meijer J.H., Albrecht U.
    Curr. Biol. 18:678-683(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  10. "Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system."
    Debruyne J.P.
    J. Genet. 87:437-446(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  11. "Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators."
    Bertolucci C., Cavallari N., Colognesi I., Aguzzi J., Chen Z., Caruso P., Foa A., Tosini G., Bernardi F., Pinotti M.
    Mol. Cell. Biol. 28:3070-3075(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  12. "NPAS2 deletion impairs responses to restricted feeding but not to metabolic challenges."
    Wu X., Wiater M.F., Ritter S.
    Physiol. Behav. 99:466-471(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  13. "Effects of the bHLH domain on axial coordination of heme in the PAS-A domain of neuronal PAS domain protein 2 (NPAS2): conversion from His119/Cys170 coordination to His119/His171 coordination."
    Uchida T., Sagami I., Shimizu T., Ishimori K., Kitagawa T.
    J. Inorg. Biochem. 108:188-195(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: HEME-BINDING, RESONANCE RAMAN SPECTROSCOPY.
  14. "Effects of NAD(P)H and its derivatives on the DNA-binding activity of NPAS2, a mammalian circadian transcription factor."
    Yoshii K., Ishijima S., Sagami I.
    Biochem. Biophys. Res. Commun. 437:386-391(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING, ENZYME REGULATION.
  15. "Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells."
    Hwang C.K., Chaurasia S.S., Jackson C.R., Chan G.C., Storm D.R., Iuvone P.M.
    J. Neurosci. 33:14989-14997(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, INDUCTION.
  16. "Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model."
    O'Neil D., Mendez-Figueroa H., Mistretta T.A., Su C., Lane R.H., Aagaard K.M.
    Mol. Genet. Metab. 110:378-387(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiNPAS2_MOUSE
AccessioniPrimary (citable) accession number: P97460
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 1, 1997
Last modified: October 29, 2014
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3