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P97460

- NPAS2_MOUSE

UniProt

P97460 - NPAS2_MOUSE

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
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    • History
      Entry version 120 (01 Oct 2014)
      Sequence version 1 (01 May 1997)
      Previous versions | rss
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    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, NR1D2, RORA, RORB and RORG, 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.

    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.

    Sites

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

    GO - Molecular functioni

    1. core promoter binding Source: UniProtKB
    2. DNA binding Source: UniProtKB
    3. metal ion binding Source: UniProtKB-KW
    4. protein binding Source: UniProtKB
    5. sequence-specific DNA binding transcription factor activity Source: InterPro
    6. 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

    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

    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. Forms a heterodimer with ARNTL/BMAL1 and this heterodimerization is required for E-box-dependent transactivation. Interacts with NCOA3, KAT2B and CREBBP By similarity. 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 NADPHAdd
    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

    MDEDEKDRAK RASRNKSEKK RRDQFNVLIK ELSSMLPGNT RKMDKTTVLE    50
    KVIGFLQKHN EVSAQTEICD IQQDWKPSFL SNEEFTQLML EALDGFVIVV 100
    TTDGSIIYVS DSITPLLGHL PADVMDQNLL NFLPEQEHSE VYKILSSHML 150
    VTDSPSPEFL KSDNDLEFYC HLLRGSLNPK EFPTYEYIKF VGNFRSYNNV 200
    PSPSCNGFDN TLSRPCHVPL GKDVCFIATV RLATPQFLKE MCVADEPLEE 250
    FTSRHSLEWK FLFLDHRAPP IIGYLPFEVL GTSGYNYYHI DDLELLARCH 300
    QHLMQFGKGK SCCYRFLTKG QQWIWLQTHY YITYHQWNSK PEFIVCTHSV 350
    VSYADVRVER RQELALEDPP TEAMHPSAVK EKDSSLEPPQ PFNALDMGAS 400
    GLPSSPSPSA SSRSSHKSSH TAMSEPTSTP TKLMAENSTT ALPRPATLPQ 450
    ELPVQGLSQA ATMPTALHSS ASCDLTKQLL LQSLPQTGLQ SPPAPVTQFS 500
    AQFSMFQTIK DQLEQRTRIL QANIRWQQEE LHKIQEQLCL VQDSNVQMFL 550
    QQPAVSLSFS STQRPAAQQQ LQQRPAAPSQ PQLVVNTPLQ GQITSTQVTN 600
    QHLLRESNVI SAQGPKPMRS SQLLPASGRS LSSLPSQFSS TASVLPPGLS 650
    LTTIAPTPQD DSQCQPSPDF GHDRQLRLLL SQPIQPMMPG SCDARQPSEV 700
    SRTGRQVKYA QSQVMFPSPD SHPTNSSAST PVLLMGQAVL HPSFPASRPS 750
    PLQPAQAQQQ PPPYLQAPTS LHSEQPDSLL LSTFSQQPGT LGYAATQSTP 800
    PQPPRPSRRV SRLSES 816
    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.
    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.
    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 1, 2014
    This is version 120 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