NPAS2 - Neuronal PAS domain-containing protein 2 - human protein (Function)
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NPAS2 »  Neuronal PAS domain-containing protein 2  (Neuronal PAS2)
Protein also known as:  Class E basic helix-loop-helix protein 9 (bHLHe9).
Gene name:  NPAS2
Entry whose protein(s) existence is based on evidence at protein level
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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.  
  • CuratedUniProtKB
GO molecular function 
Core promoter bindingdefinition[GO:0001047]  
  • ISSOrtholog Curator
DNA bindingdefinition[GO:0003677]  
  • IDAUniProtKB
Hsp90 protein bindingdefinition[GO:0051879]  
Metal ion bindingdefinition[GO:0046872]  
  • IEAUniProtKB KW
Protein bindingdefinition[GO:0005515]  
  • IPIUniProtKB
Protein dimerization activitydefinition[GO:0046983] silver  
  • IEAInterPro 2 GO
Sequence-specific DNA binding transcription factor activitydefinition[GO:0003700] silver  
  • IEAInterPro 2 GO
Signal transducer activitydefinition[GO:0004871] silver  
  • IEAInterPro 2 GO
GO biological process 
Cellular response to DNA damage stimulusdefinition[GO:0006974]  
  • IEAUniProtKB KW
Central nervous system developmentdefinition[GO:0007417]  
Circadian regulation of gene expressiondefinition[GO:0032922]  
  • ISSOrtholog Curator
Circadian sleep/wake cycledefinition[GO:0042745] silver  
  • IEAOrtholog Compara
Locomotor rhythmdefinition[GO:0045475] silver  
  • IEAOrtholog Compara
Negative regulation of cell deathdefinition[GO:0060548]  
  • IMPUniProtKB
Positive regulation of DNA repairdefinition[GO:0045739]  
  • IMPUniProtKB
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944]  
Positive regulation of transcription, DNA-templateddefinition[GO:0045893]  
  • IMPUniProtKB
Regulation of response to DNA damage stimulusdefinition[GO:2001020]  
  • IMPUniProtKB
Response to redox statedefinition[GO:0051775]  
  • IDAUniProtKB
Signal transductiondefinition[GO:0007165] silver  
  • IEAInterPro 2 GO
Transcription, DNA-templateddefinition[GO:0006351]  
  • IEAUniProtKB KW
Enzymatic activity 
It requires the following cofactor
Binds heme.  
  • CuratedUniProtKB
It is regulated in the following manner
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).  
  • CuratedUniProtKB
According to KEGG, this protein belongs to the following pathway:
Circadian rhythm - mammal  hsa04710+4862  
According to Reactome, this protein belongs to the following pathways:
BMAL1:CLOCK,NPAS2 activates circadian gene expression  REACT_111118  
Circadian Clock  REACT_24941  
PPARA activates gene expression  REACT_116145  
REV-ERBA represses gene expression  REACT_118789  
RORA activates circadian gene expression  REACT_118659  


Biological process 
Biological rhythms  definition   [KW-0090]
DNA damage  definition   [KW-0227]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Activator  definition   [KW-0010]
Technical term 
Reference proteome  definition   [KW-1185]

Further external links

GeneWiki: NPAS2
GenomeRNAi: 4862
PRO: PR:Q99743