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Protein

Neuronal PAS domain-containing protein 2

Gene

Npas2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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

heme2 Publications

Activity 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)DescriptionActionsGraphical viewLength
Metal bindingi119Iron (heme B axial ligand)2 Publications1
Metal bindingi171Iron (heme B axial ligand)2 Publications1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding
Biological processBiological rhythms, DNA damage, Transcription, Transcription regulation
LigandHeme, Iron, Metal-binding

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:109232 Npas2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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 dysregulation in the lipid and fatty acid metabolism pathways and a significant reduction in daytime contrast sensitivity.5 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi119H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. 1 Publication1
Mutagenesisi171H → A: Significant decrease in DNA binding affinity resulting in a loss of the transcriptional activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001274071 – 816Neuronal PAS domain-containing protein 2Add BLAST816

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP97460
PaxDbiP97460
PRIDEiP97460

PTM databases

PhosphoSitePlusiP97460

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

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

GO - Molecular functioni

Protein-protein interaction databases

IntActiP97460, 1 interactor
MINTiP97460
STRINGi10090.ENSMUSP00000054719

Structurei

3D structure databases

ProteinModelPortaliP97460
SMRiP97460
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini9 – 59bHLHPROSITE-ProRule annotationAdd BLAST51
Domaini82 – 152PAS 1PROSITE-ProRule annotationAdd BLAST71
Domaini237 – 307PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini311 – 354PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 61Sufficient for heterodimer formation with ARNTL/BMAL1, E-box binding and for the effect of NADPH1 PublicationAdd BLAST61

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410IQ5V Eukaryota
ENOG410Y7Z8 LUCA
HOGENOMiHOG000234382
HOVERGENiHBG050997
InParanoidiP97460
KOiK09026
PhylomeDBiP97460

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
TIGRFAMsiTIGR00229 sensory_box, 1 hit
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3X9B7G3X9B7_MOUSE
Neuronal PAS domain protein 2
Npas2 mCG_8437
816Annotation score:
G3UYV8G3UYV8_MOUSE
Neuronal PAS domain-containing prot...
Npas2
60Annotation score:

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U77969 mRNA Translation: AAB47249.1
CCDSiCCDS48244.1
RefSeqiNP_032745.2, NM_008719.2
UniGeneiMm.2380

Genome annotation databases

GeneIDi18143
KEGGimmu:18143

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U77969 mRNA Translation: AAB47249.1
CCDSiCCDS48244.1
RefSeqiNP_032745.2, NM_008719.2
UniGeneiMm.2380

3D structure databases

ProteinModelPortaliP97460
SMRiP97460
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP97460, 1 interactor
MINTiP97460
STRINGi10090.ENSMUSP00000054719

PTM databases

PhosphoSitePlusiP97460

Proteomic databases

MaxQBiP97460
PaxDbiP97460
PRIDEiP97460

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi18143
KEGGimmu:18143

Organism-specific databases

CTDi4862
MGIiMGI:109232 Npas2

Phylogenomic databases

eggNOGiENOG410IQ5V Eukaryota
ENOG410Y7Z8 LUCA
HOGENOMiHOG000234382
HOVERGENiHBG050997
InParanoidiP97460
KOiK09026
PhylomeDBiP97460

Miscellaneous databases

PROiPR:P97460
SOURCEiSearch...

Gene expression databases

CleanExiMM_NPAS2

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
TIGRFAMsiTIGR00229 sensory_box, 1 hit
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNPAS2_MOUSE
AccessioniPrimary (citable) accession number: P97460
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 1, 1997
Last modified: November 7, 2018
This is version 149 of the entry and version 1 of the sequence. See 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
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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