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Q99743 (NPAS2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 139. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | 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
Alternative name(s):
Basic-helix-loop-helix-PAS protein MOP4
Class E basic helix-loop-helix protein 9
Short name=bHLHe9
Member of PAS protein 4
PAS domain-containing protein 4
Gene names
Name:NPAS2
Synonyms:BHLHE9, MOP4, PASD4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length824 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.5 Ref.6 Ref.7 Ref.8 Ref.9

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 By similarity.

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, CREBBP and EP300. Ref.7

Subcellular location

Nucleus Ref.7.

Polymorphism

Variants in NPAS2 show a susceptibility to seasonal affective disorder (SAD) [MIM:608516]. SAD is a depressive condition resulting from seasonal changes, and with diurnal preference.

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
   Coding sequence diversityPolymorphism
   DomainRepeat
   LigandDNA-binding
Heme
Iron
Metal-binding
   Molecular functionActivator
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular lipid metabolic process

Traceable author statement. Source: Reactome

cellular response to DNA damage stimulus

Inferred from electronic annotation. Source: UniProtKB-KW

central nervous system development

Traceable author statement Ref.1. Source: ProtInc

circadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

circadian sleep/wake cycle

Inferred from electronic annotation. Source: Ensembl

locomotor rhythm

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell death

Inferred from mutant phenotype Ref.9. Source: UniProtKB

positive regulation of DNA repair

Inferred from mutant phenotype Ref.9. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from genetic interaction PubMed 9576906. Source: MGI

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.6. Source: UniProtKB

regulation of response to DNA damage stimulus

Inferred from mutant phenotype Ref.9. Source: UniProtKB

response to redox state

Inferred from direct assay Ref.6. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.7. Source: UniProtKB

transcription factor complex

Inferred from physical interaction PubMed 9576906. Source: MGI

   Molecular_functionDNA binding

Inferred from direct assay Ref.6. Source: UniProtKB

Hsp90 protein binding

Inferred from direct assay Ref.4. Source: BHF-UCL

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.7. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Traceable author statement Ref.1. Source: ProtInc

signal transducer activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 824824Neuronal PAS domain-containing protein 2
PRO_0000127406

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 By similarity

Sites

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

Natural variations

Natural variant3941T → A Associated with non-Hodgkin's lymphoma and breast cancer risk. Ref.1 Ref.3 Ref.4 Ref.12 Ref.13
Corresponds to variant rs2305160 [ dbSNP | Ensembl ].
VAR_029078
Natural variant4711S → L Susceptibility to seasonal affective disorder (SAD) and diurnal preference. Ref.1 Ref.11
Corresponds to variant rs11541353 [ dbSNP | Ensembl ].
VAR_029079

Experimental info

Sequence conflict511K → E in AAC51211. Ref.4
Sequence conflict1641S → G in AAC51211. Ref.4
Sequence conflict3081K → T in AAB47250. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q99743 [UniParc].

Last modified November 2, 2010. Version 3.
Checksum: 679919FCDD3AFDEB

FASTA82491,791
        10         20         30         40         50         60 
MDEDEKDRAK RASRNKSEKK RRDQFNVLIK ELSSMLPGNT RKMDKTTVLE KVIGFLQKHN 

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

       130        140        150        160        170        180 
PSDVMDQNLL NFLPEQEHSE VYKILSSHML VTDSPSPEYL KSDSDLEFYC HLLRGSLNPK 

       190        200        210        220        230        240 
EFPTYEYIKF VGNFRSYNNV PSPSCNGFDN TLSRPCRVPL GKEVCFIATV RLATPQFLKE 

       250        260        270        280        290        300 
MCIVDEPLEE FTSRHSLEWK FLFLDHRAPP IIGYLPFEVL GTSGYDYYHI DDLELLARCH 

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

       370        380        390        400        410        420 
RQELALEDPP SEALHSSALK DKGSSLEPRQ HFNTLDVGAS GLNTSHSPSA SSRSSHKSSH 

       430        440        450        460        470        480 
TAMSEPTSTP TKLMAEASTP ALPRSATLPQ ELPVPGLSQA ATMPAPLPSP SSCDLTQQLL 

       490        500        510        520        530        540 
PQTVLQSTPA PMAQFSAQFS MFQTIKDQLE QRTRILQANI RWQQEELHKI QEQLCLVQDS 

       550        560        570        580        590        600 
NVQMFLQQPA VSLSFSSTQR PEAQQQLQQR SAAVTQPQLG AGPQLPGQIS SAQVTSQHLL 

       610        620        630        640        650        660 
RESSVISTQG PKPMRSSQLM QSSGRSGSSL VSPFSSATAA LPPSLNLTTP ASTSQDASQC 

       670        680        690        700        710        720 
QPSPDFSHDR QLRLLLSQPI QPMMPGSCDA RQPSEVSRTG RQVKYAQSQT VFQNPDAHPA 

       730        740        750        760        770        780 
NSSSAPMPVL LMGQAVLHPS FPASQPSPLQ PAQARQQPPQ HYLQVQAPTS LHSEQQDSLL 

       790        800        810        820 
LSTYSQQPGT LGYPQPPPAQ PQPLRPPRRV SSLSESSGLQ QPPR 

« Hide

References

« Hide 'large scale' 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], VARIANTS ALA-394 AND LEU-471.
[2]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ALA-394.
Tissue: Lung.
[4]"Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway."
Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., Pray-Grant M., Perdew G.H., Bradfield C.A.
J. Biol. Chem. 272:8581-8593(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-626, VARIANT ALA-394.
[5]"NPAS2: an analog of clock operative in the mammalian forebrain."
Reick M., Garcia J.A., Dudley C., McKnight S.L.
Science 293:506-509(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors."
Rutter J., Reick M., Wu L.C., McKnight S.L.
Science 293:510-514(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DNA-BINDING.
[7]"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: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH NCOA3; KAT2B; CREBBP AND EP300.
[8]"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.
[9]"The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response."
Hoffman A.E., Zheng T., Ba Y., Zhu Y.
Mol. Cancer Res. 6:1461-1468(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"Metabolism and the circadian clock converge."
Eckel-Mahan K., Sassone-Corsi P.
Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[11]"Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference."
Johansson C., Willeit M., Smedh C., Ekholm J., Paunio T., Kieseppa T., Lichtermann D., Praschak-Rieder N., Neumeister A., Nilsson L.G., Kasper S., Peltonen L., Adolfsson R., Schalling M., Partonen T.
Neuropsychopharmacology 28:734-739(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: ASSOCIATION OF VARIANT LEU-471 WITH SAD.
[12]"Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma."
Zhu Y., Leaderer D., Guss C., Brown H.N., Zhang Y., Boyle P., Stevens R.G., Hoffman A., Qin Q., Han X., Zheng T.
Int. J. Cancer 120:432-435(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-394.
[13]"Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk."
Zhu Y., Stevens R.G., Leaderer D., Hoffman A., Holford T., Zhang Y., Brown H.N., Zheng T.
Breast Cancer Res. Treat. 107:421-425(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-394.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U77970 mRNA. Translation: AAB47250.1.
AC016738 Genomic DNA. Translation: AAY14822.1.
AC092168 Genomic DNA. No translation available.
AC106891 Genomic DNA. Translation: AAX88966.1.
BC051351 mRNA. Translation: AAH51351.2.
BC072383 mRNA. Translation: AAH72383.1.
U51625 mRNA. Translation: AAC51211.1.
CCDSCCDS2048.1.
RefSeqNP_002509.2. NM_002518.3.
UniGeneHs.156832.
Hs.705895.

3D structure databases

ProteinModelPortalQ99743.
SMRQ99743. Positions 6-359.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110923. 13 interactions.
IntActQ99743. 8 interactions.
STRING9606.ENSP00000338283.

PTM databases

PhosphoSiteQ99743.

Polymorphism databases

DMDM311033423.

Proteomic databases

PaxDbQ99743.
PRIDEQ99743.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000335681; ENSP00000338283; ENSG00000170485.
GeneID4862.
KEGGhsa:4862.
UCSCuc002tap.1. human.

Organism-specific databases

CTD4862.
GeneCardsGC02P101436.
H-InvDBHIX0200274.
HGNCHGNC:7895. NPAS2.
HPAHPA019674.
MIM603347. gene.
608516. phenotype.
neXtProtNX_Q99743.
PharmGKBPA31696.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG300360.
HOVERGENHBG050997.
InParanoidQ99743.
KOK09026.
PhylomeDBQ99743.
TreeFamTF324568.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
REACT_24941. Circadian Clock.

Gene expression databases

ArrayExpressQ99743.
BgeeQ99743.
CleanExHS_NPAS2.
GenevestigatorQ99743.

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. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSNPAS2. human.
GeneWikiNPAS2.
GenomeRNAi4862.
NextBio18730.
PROQ99743.
SOURCESearch...

Entry information

Entry nameNPAS2_HUMAN
AccessionPrimary (citable) accession number: Q99743
Secondary accession number(s): Q4ZFV9 expand/collapse secondary AC list , Q53SQ3, Q86V96, Q99629
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: November 2, 2010
Last modified: July 9, 2014
This is version 139 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM