UniProtKB - Q99743 (NPAS2_HUMAN)
Protein
Neuronal PAS domain-containing protein 2
Gene
NPAS2
Organism
Homo sapiens (Human)
Status
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. Controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter (By similarity). Mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum (By similarity).By similarity5 Publications
Cofactori
hemeBy similarity
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.By similarity
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Metal bindingi | 119 | Iron (heme B axial ligand)By similarity | 1 | |
Metal bindingi | 171 | Iron (heme B axial ligand)By similarity | 1 |
GO - Molecular functioni
- DNA binding Source: UniProtKB
- DNA-binding transcription factor activity Source: ProtInc
- DNA-binding transcription factor activity, RNA polymerase II-specific Source: NTNU_SB
- Hsp90 protein binding Source: BHF-UCL
- metal ion binding Source: UniProtKB-KW
- protein dimerization activity Source: InterPro
- RNA polymerase II cis-regulatory region sequence-specific DNA binding Source: UniProtKB
- sequence-specific double-stranded DNA binding Source: ARUK-UCL
GO - Biological processi
- cellular response to DNA damage stimulus Source: UniProtKB-KW
- central nervous system development Source: ProtInc
- circadian regulation of gene expression Source: UniProtKB
- circadian rhythm Source: Reactome
- negative regulation of cell death Source: UniProtKB
- positive regulation of behavioral fear response Source: UniProtKB
- positive regulation of DNA repair Source: UniProtKB
- positive regulation of transcription, DNA-templated Source: UniProtKB
- positive regulation of transcription by RNA polymerase II Source: MGI
- regulation of lipid metabolic process Source: Reactome
- regulation of response to DNA damage stimulus Source: UniProtKB
- regulation of transcription by RNA polymerase II Source: GO_Central
- response to drug Source: UniProtKB
- response to redox state Source: UniProtKB
Keywordsi
Molecular function | Activator, DNA-binding |
Biological process | Biological rhythms, DNA damage, Transcription, Transcription regulation |
Ligand | Heme, Iron, Metal-binding |
Enzyme and pathway databases
PathwayCommonsi | Q99743 |
Reactomei | R-HSA-1368108, BMAL1:CLOCK,NPAS2 activates circadian gene expression R-HSA-1989781, PPARA activates gene expression R-HSA-400253, Circadian Clock |
Names & Taxonomyi
Protein namesi | Recommended name: Neuronal PAS domain-containing protein 2Short 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 namesi | Name:NPAS2 Synonyms:BHLHE9, MOP4, PASD4 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:7895, NPAS2 |
MIMi | 603347, gene |
neXtProti | NX_Q99743 |
VEuPathDBi | HostDB:ENSG00000170485.16 |
Subcellular locationi
Nucleus
- Nucleus PROSITE-ProRule annotation1 Publication
Cytosol
- cytosol Source: HPA
Nucleus
- CLOCK-BMAL transcription complex Source: GO_Central
- nuclear chromatin Source: NTNU_SB
- nucleoplasm Source: HPA
- nucleus Source: UniProtKB
Other locations
- transcription regulator complex Source: MGI
Keywords - Cellular componenti
NucleusPathology & Biotechi
Organism-specific databases
DisGeNETi | 4862 |
MIMi | 608516, phenotype |
OpenTargetsi | ENSG00000170485 |
PharmGKBi | PA31696 |
Miscellaneous databases
Pharosi | Q99743, Tbio |
Genetic variation databases
BioMutai | NPAS2 |
DMDMi | 311033423 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000127406 | 1 – 824 | Neuronal PAS domain-containing protein 2Add BLAST | 824 |
Proteomic databases
jPOSTi | Q99743 |
MassIVEi | Q99743 |
PaxDbi | Q99743 |
PeptideAtlasi | Q99743 |
PRIDEi | Q99743 |
ProteomicsDBi | 78454 |
PTM databases
iPTMneti | Q99743 |
PhosphoSitePlusi | Q99743 |
Expressioni
Gene expression databases
Bgeei | ENSG00000170485, Expressed in lower esophagus mucosa and 220 other tissues |
ExpressionAtlasi | Q99743, baseline and differential |
Genevisiblei | Q99743, HS |
Organism-specific databases
HPAi | ENSG00000170485, Low tissue specificity |
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, CREBBP and EP300.
1 PublicationBinary interactionsi
Hide detailsQ99743
GO - Molecular functioni
- Hsp90 protein binding Source: BHF-UCL
- protein dimerization activity Source: InterPro
Protein-protein interaction databases
BioGRIDi | 110923, 38 interactors |
CORUMi | Q99743 |
DIPi | DIP-60821N |
IntActi | Q99743, 24 interactors |
STRINGi | 9606.ENSP00000338283 |
Miscellaneous databases
RNActi | Q99743, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 9 – 59 | bHLHPROSITE-ProRule annotationAdd BLAST | 51 | |
Domaini | 82 – 152 | PAS 1PROSITE-ProRule annotationAdd BLAST | 71 | |
Domaini | 237 – 307 | PAS 2PROSITE-ProRule annotationAdd BLAST | 71 | |
Domaini | 311 – 354 | PACAdd BLAST | 44 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 61 | Sufficient for heterodimer formation with ARNTL/BMAL1, E-box binding and for the effect of NADPHBy similarityAdd BLAST | 61 |
Keywords - Domaini
RepeatPhylogenomic databases
eggNOGi | KOG3561, Eukaryota |
GeneTreei | ENSGT00940000160744 |
HOGENOMi | CLU_010044_2_2_1 |
InParanoidi | Q99743 |
OMAi | QPSCELL |
OrthoDBi | 205871at2759 |
PhylomeDBi | Q99743 |
TreeFami | TF324568 |
Family and domain databases
CDDi | cd00083, HLH, 1 hit cd00130, PAS, 2 hits |
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00010, HLH, 1 hit PF00989, PAS, 1 hit |
PRINTSi | PR00785, NCTRNSLOCATR |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00086, PAC, 1 hit SM00091, PAS, 2 hits |
SUPFAMi | SSF47459, SSF47459, 1 hit SSF55785, SSF55785, 2 hits |
TIGRFAMsi | TIGR00229, sensory_box, 1 hit |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS50112, PAS, 2 hits |
(1+)i Sequence
Sequence statusi: Complete.
This entry has 1 described isoform and 5 potential isoforms that are computationally mapped.Show allAlign All
Q99743-1 [UniParc]FASTAAdd to basket
10 20 30 40 50
MDEDEKDRAK RASRNKSEKK RRDQFNVLIK ELSSMLPGNT RKMDKTTVLE
60 70 80 90 100
KVIGFLQKHN EVSAQTEICD IQQDWKPSFL SNEEFTQLML EALDGFIIAV
110 120 130 140 150
TTDGSIIYVS DSITPLLGHL PSDVMDQNLL NFLPEQEHSE VYKILSSHML
160 170 180 190 200
VTDSPSPEYL KSDSDLEFYC HLLRGSLNPK EFPTYEYIKF VGNFRSYNNV
210 220 230 240 250
PSPSCNGFDN TLSRPCRVPL GKEVCFIATV RLATPQFLKE MCIVDEPLEE
260 270 280 290 300
FTSRHSLEWK FLFLDHRAPP IIGYLPFEVL GTSGYDYYHI DDLELLARCH
310 320 330 340 350
QHLMQFGKGK SCCYRFLTKG QQWIWLQTHY YITYHQWNSK PEFIVCTHSV
360 370 380 390 400
VSYADVRVER RQELALEDPP SEALHSSALK DKGSSLEPRQ HFNTLDVGAS
410 420 430 440 450
GLNTSHSPSA SSRSSHKSSH TAMSEPTSTP TKLMAEASTP ALPRSATLPQ
460 470 480 490 500
ELPVPGLSQA ATMPAPLPSP SSCDLTQQLL PQTVLQSTPA PMAQFSAQFS
510 520 530 540 550
MFQTIKDQLE QRTRILQANI RWQQEELHKI QEQLCLVQDS NVQMFLQQPA
560 570 580 590 600
VSLSFSSTQR PEAQQQLQQR SAAVTQPQLG AGPQLPGQIS SAQVTSQHLL
610 620 630 640 650
RESSVISTQG PKPMRSSQLM QSSGRSGSSL VSPFSSATAA LPPSLNLTTP
660 670 680 690 700
ASTSQDASQC QPSPDFSHDR QLRLLLSQPI QPMMPGSCDA RQPSEVSRTG
710 720 730 740 750
RQVKYAQSQT VFQNPDAHPA NSSSAPMPVL LMGQAVLHPS FPASQPSPLQ
760 770 780 790 800
PAQARQQPPQ HYLQVQAPTS LHSEQQDSLL LSTYSQQPGT LGYPQPPPAQ
810 820
PQPLRPPRRV SSLSESSGLQ QPPR
Computationally mapped potential isoform sequencesi
There are 5 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketH7C0Z2 | H7C0Z2_HUMAN | Neuronal PAS domain-containing prot... | NPAS2 | 207 | Annotation score: | ||
H7BZA3 | H7BZA3_HUMAN | Neuronal PAS domain-containing prot... | NPAS2 | 258 | Annotation score: | ||
H7C0J4 | H7C0J4_HUMAN | Neuronal PAS domain-containing prot... | NPAS2 | 107 | Annotation score: | ||
H7BZY5 | H7BZY5_HUMAN | Neuronal PAS domain-containing prot... | NPAS2 | 202 | Annotation score: | ||
H7C080 | H7C080_HUMAN | Neuronal PAS domain-containing prot... | NPAS2 | 269 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 51 | K → E in AAC51211 (PubMed:9079689).Curated | 1 | |
Sequence conflicti | 164 | S → G in AAC51211 (PubMed:9079689).Curated | 1 | |
Sequence conflicti | 308 | K → T in AAB47250 (PubMed:9012850).Curated | 1 |
Polymorphismi
Variants in NPAS2 show a susceptibility to seasonal affective disorder (SAD) [MIMi:608516]. SAD is a depressive condition resulting from seasonal changes, and with diurnal preference.1 Publication
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_029078 | 394 | T → A Associated with non-Hodgkin's lymphoma and breast cancer risk. 5 PublicationsCorresponds to variant dbSNP:rs2305160Ensembl. | 1 | |
Natural variantiVAR_029079 | 471 | S → L Susceptibility to seasonal affective disorder (SAD) and diurnal preference. 1 PublicationCorresponds to variant dbSNP:rs11541353Ensembl. | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | 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 |
CCDSi | CCDS2048.1 |
RefSeqi | NP_002509.2, NM_002518.3 |
Genome annotation databases
Ensembli | ENST00000335681; ENSP00000338283; ENSG00000170485 |
GeneIDi | 4862 |
KEGGi | hsa:4862 |
UCSCi | uc002tap.2, human |
Similar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | 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 |
CCDSi | CCDS2048.1 |
RefSeqi | NP_002509.2, NM_002518.3 |
3D structure databases
SMRi | Q99743 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 110923, 38 interactors |
CORUMi | Q99743 |
DIPi | DIP-60821N |
IntActi | Q99743, 24 interactors |
STRINGi | 9606.ENSP00000338283 |
PTM databases
iPTMneti | Q99743 |
PhosphoSitePlusi | Q99743 |
Genetic variation databases
BioMutai | NPAS2 |
DMDMi | 311033423 |
Proteomic databases
jPOSTi | Q99743 |
MassIVEi | Q99743 |
PaxDbi | Q99743 |
PeptideAtlasi | Q99743 |
PRIDEi | Q99743 |
ProteomicsDBi | 78454 |
Protocols and materials databases
Antibodypediai | 32870, 232 antibodies |
Genome annotation databases
Ensembli | ENST00000335681; ENSP00000338283; ENSG00000170485 |
GeneIDi | 4862 |
KEGGi | hsa:4862 |
UCSCi | uc002tap.2, human |
Organism-specific databases
CTDi | 4862 |
DisGeNETi | 4862 |
GeneCardsi | NPAS2 |
HGNCi | HGNC:7895, NPAS2 |
HPAi | ENSG00000170485, Low tissue specificity |
MIMi | 603347, gene 608516, phenotype |
neXtProti | NX_Q99743 |
OpenTargetsi | ENSG00000170485 |
PharmGKBi | PA31696 |
VEuPathDBi | HostDB:ENSG00000170485.16 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG3561, Eukaryota |
GeneTreei | ENSGT00940000160744 |
HOGENOMi | CLU_010044_2_2_1 |
InParanoidi | Q99743 |
OMAi | QPSCELL |
OrthoDBi | 205871at2759 |
PhylomeDBi | Q99743 |
TreeFami | TF324568 |
Enzyme and pathway databases
PathwayCommonsi | Q99743 |
Reactomei | R-HSA-1368108, BMAL1:CLOCK,NPAS2 activates circadian gene expression R-HSA-1989781, PPARA activates gene expression R-HSA-400253, Circadian Clock |
Miscellaneous databases
BioGRID-ORCSi | 4862, 6 hits in 896 CRISPR screens |
ChiTaRSi | NPAS2, human |
GeneWikii | NPAS2 |
GenomeRNAii | 4862 |
Pharosi | Q99743, Tbio |
PROi | PR:Q99743 |
RNActi | Q99743, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000170485, Expressed in lower esophagus mucosa and 220 other tissues |
ExpressionAtlasi | Q99743, baseline and differential |
Genevisiblei | Q99743, HS |
Family and domain databases
CDDi | cd00083, HLH, 1 hit cd00130, PAS, 2 hits |
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00010, HLH, 1 hit PF00989, PAS, 1 hit |
PRINTSi | PR00785, NCTRNSLOCATR |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00086, PAC, 1 hit SM00091, PAS, 2 hits |
SUPFAMi | SSF47459, SSF47459, 1 hit SSF55785, SSF55785, 2 hits |
TIGRFAMsi | TIGR00229, sensory_box, 1 hit |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS50112, PAS, 2 hits |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | NPAS2_HUMAN | |
Accessioni | Q99743Primary (citable) accession number: Q99743 Secondary accession number(s): Q4ZFV9 Q99629 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | December 15, 1998 |
Last sequence update: | November 2, 2010 | |
Last modified: | February 10, 2021 | |
This is version 191 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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. |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - Human chromosome 2
Human chromosome 2: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants