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P97460 (NPAS2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Neuronal PAS domain-containing protein 2

Short name=Neuronal PAS2
Gene names
Name:Npas2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length816 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.15 Ref.16

Cofactor

Binds heme.

Enzyme regulation

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.

Subunit structure

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. Ref.3 Ref.5

Subcellular location

Nucleus Ref.5.

Tissue specificity

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. Ref.1 Ref.7 Ref.15

Developmental stage

First detected 3 days after birth. Ref.1

Induction

Expression in the retinal ganglion cells and heart oscillates in a circadian manner. Ref.3 Ref.15

Disruption phenotype

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. Ref.6 Ref.7 Ref.12 Ref.15 Ref.16

Sequence similarities

Contains 1 bHLH (basic helix-loop-helix) domain.

Contains 1 PAC (PAS-associated C-terminal) domain.

Contains 2 PAS (PER-ARNT-SIM) domains.

Ontologies

Keywords
   Biological processBiological rhythms
DNA damage
Transcription
Transcription regulation
   Cellular componentNucleus
   DomainRepeat
   LigandDNA-binding
Heme
Iron
Metal-binding
   Molecular functionActivator
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to DNA damage stimulus

Inferred from electronic annotation. Source: UniProtKB-KW

circadian regulation of gene expression

Inferred from mutant phenotype Ref.11Ref.15. Source: UniProtKB

circadian rhythm

Inferred from expression pattern Ref.3. Source: UniProtKB

circadian sleep/wake cycle

Inferred from mutant phenotype Ref.2. Source: MGI

locomotor rhythm

Inferred from mutant phenotype Ref.2. Source: MGI

negative regulation of cell death

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of DNA repair

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.11Ref.15. Source: UniProtKB

regulation of circadian rhythm

Inferred from mutant phenotype Ref.15. Source: UniProtKB

regulation of response to DNA damage stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

response to redox state

Inferred from direct assay Ref.14. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

transcription factor complex

Inferred from electronic annotation. Source: InterPro

   Molecular_functionDNA binding

Inferred from direct assay Ref.14. Source: UniProtKB

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction Ref.3. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: InterPro

signal transducer activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 816816Neuronal PAS domain-containing protein 2
PRO_0000127407

Regions

Domain9 – 5951bHLH
Domain82 – 15271PAS 1
Domain237 – 30771PAS 2
Domain311 – 35444PAC
Region1 – 6161Sufficient for heterodimer formation with ARNTL/BMAL1, E-box binding and for the effect of NADPH

Sites

Metal binding1191Iron (heme B axial ligand)
Metal binding1711Iron (heme B axial ligand)

Experimental info

Mutagenesis1191H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. Ref.8
Mutagenesis1711H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. Ref.8

Sequences

Sequence LengthMass (Da)Tools
P97460 [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: 7E5CF0641CFDC1DD

FASTA81690,916
        10         20         30         40         50         60 
MDEDEKDRAK RASRNKSEKK RRDQFNVLIK ELSSMLPGNT RKMDKTTVLE KVIGFLQKHN 

        70         80         90        100        110        120 
EVSAQTEICD IQQDWKPSFL SNEEFTQLML EALDGFVIVV TTDGSIIYVS DSITPLLGHL 

       130        140        150        160        170        180 
PADVMDQNLL NFLPEQEHSE VYKILSSHML VTDSPSPEFL KSDNDLEFYC HLLRGSLNPK 

       190        200        210        220        230        240 
EFPTYEYIKF VGNFRSYNNV PSPSCNGFDN TLSRPCHVPL GKDVCFIATV RLATPQFLKE 

       250        260        270        280        290        300 
MCVADEPLEE FTSRHSLEWK FLFLDHRAPP IIGYLPFEVL GTSGYNYYHI DDLELLARCH 

       310        320        330        340        350        360 
QHLMQFGKGK SCCYRFLTKG QQWIWLQTHY YITYHQWNSK PEFIVCTHSV VSYADVRVER 

       370        380        390        400        410        420 
RQELALEDPP TEAMHPSAVK EKDSSLEPPQ PFNALDMGAS GLPSSPSPSA SSRSSHKSSH 

       430        440        450        460        470        480 
TAMSEPTSTP TKLMAENSTT ALPRPATLPQ ELPVQGLSQA ATMPTALHSS ASCDLTKQLL 

       490        500        510        520        530        540 
LQSLPQTGLQ SPPAPVTQFS AQFSMFQTIK DQLEQRTRIL QANIRWQQEE LHKIQEQLCL 

       550        560        570        580        590        600 
VQDSNVQMFL QQPAVSLSFS STQRPAAQQQ LQQRPAAPSQ PQLVVNTPLQ GQITSTQVTN 

       610        620        630        640        650        660 
QHLLRESNVI SAQGPKPMRS SQLLPASGRS LSSLPSQFSS TASVLPPGLS LTTIAPTPQD 

       670        680        690        700        710        720 
DSQCQPSPDF GHDRQLRLLL SQPIQPMMPG SCDARQPSEV SRTGRQVKYA QSQVMFPSPD 

       730        740        750        760        770        780 
SHPTNSSAST PVLLMGQAVL HPSFPASRPS PLQPAQAQQQ PPPYLQAPTS LHSEQPDSLL 

       790        800        810 
LSTFSQQPGT LGYAATQSTP PQPPRPSRRV SRLSES 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U77969 mRNA. Translation: AAB47249.1.
CCDSCCDS48244.1.
RefSeqNP_032745.2. NM_008719.2.
UniGeneMm.2380.

3D structure databases

ProteinModelPortalP97460.
SMRP97460. Positions 6-359.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActP97460. 1 interaction.

PTM databases

PhosphoSiteP97460.

Proteomic databases

PaxDbP97460.
PRIDEP97460.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID18143.
KEGGmmu:18143.

Organism-specific databases

CTD4862.
MGIMGI:109232. Npas2.

Phylogenomic databases

eggNOGNOG300360.
HOGENOMHOG000234382.
HOVERGENHBG050997.
InParanoidP97460.
KOK09026.
PhylomeDBP97460.

Enzyme and pathway databases

ReactomeREACT_200794. Mus musculus biological processes.

Gene expression databases

CleanExMM_NPAS2.
GenevestigatorP97460.

Family and domain databases

Gene3D4.10.280.10. 1 hit.
InterProIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSPR00785. NCTRNSLOCATR.
SMARTSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsTIGR00229. sensory_box. 1 hit.
PROSITEPS50888. BHLH. 1 hit.
PS50112. PAS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio293396.
PROP97460.
SOURCESearch...

Entry information

Entry nameNPAS2_MOUSE
AccessionPrimary (citable) accession number: P97460
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 1, 1997
Last modified: July 9, 2014
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot