Q99743 (NPAS2_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 139. History...
Names and origin
|Protein names||Recommended name:|
Neuronal PAS domain-containing protein 2
Short name=Neuronal PAS2
Basic-helix-loop-helix-PAS protein MOP4
Class E basic helix-loop-helix protein 9
Member of PAS protein 4
PAS domain-containing protein 4
|Organism||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||824 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
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.
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
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.
Contains 1 bHLH (basic helix-loop-helix) domain.
Contains 1 PAC (PAS-associated C-terminal) domain.
Contains 2 PAS (PER-ARNT-SIM) domains.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 824||824||Neuronal PAS domain-containing protein 2||PRO_0000127406|
|Domain||9 – 59||51||bHLH|
|Domain||82 – 152||71||PAS 1|
|Domain||237 – 307||71||PAS 2|
|Domain||311 – 354||44||PAC|
|Region||1 – 61||61||Sufficient for heterodimer formation with ARNTL/BMAL1, E-box binding and for the effect of NADPH By similarity|
|Metal binding||119||1||Iron (heme B axial ligand) By similarity|
|Metal binding||171||1||Iron (heme B axial ligand) By similarity|
|Natural variant||394||1||T → 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 ].
|Natural variant||471||1||S → L Susceptibility to seasonal affective disorder (SAD) and diurnal preference. Ref.1 Ref.11|
Corresponds to variant rs11541353 [ dbSNP | Ensembl ].
|Sequence conflict||51||1||K → E in AAC51211. Ref.4|
|Sequence conflict||164||1||S → G in AAC51211. Ref.4|
|Sequence conflict||308||1||K → T in AAB47250. Ref.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.
|||"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. Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|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.
|RefSeq||NP_002509.2. NM_002518.3. |
3D structure databases
|SMR||Q99743. Positions 6-359. |
Protein-protein interaction databases
|BioGrid||110923. 13 interactions.|
|IntAct||Q99743. 8 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000335681; ENSP00000338283; ENSG00000170485. |
|UCSC||uc002tap.1. human. |
|HGNC||HGNC:7895. NPAS2. |
|MIM||603347. gene. |
Enzyme and pathway databases
|Reactome||REACT_111217. Metabolism. |
REACT_24941. Circadian Clock.
Gene expression databases
Family and domain databases
|Gene3D||4.10.280.10. 1 hit. |
|InterPro||IPR011598. bHLH_dom. |
|Pfam||PF00010. HLH. 1 hit. |
PF00989. PAS. 1 hit.
|PRINTS||PR00785. NCTRNSLOCATR. |
|SMART||SM00353. HLH. 1 hit. |
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
|SUPFAM||SSF47459. SSF47459. 1 hit. |
SSF55785. SSF55785. 2 hits.
|TIGRFAMs||TIGR00229. sensory_box. 1 hit. |
|PROSITE||PS50888. BHLH. 1 hit. |
PS50112. PAS. 2 hits.
|ChiTaRS||NPAS2. human. |
|Accession||Primary (citable) accession number: Q99743|
Secondary accession number(s): Q4ZFV9 Q99629
|Entry status||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.|
Index of protein domains and families
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