P97460NPAS2_MOUSENeuronal PAS domain-containing protein 2Neuronal PAS2Npas2Mus musculusMouseEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMusMolecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system.NUCLEOTIDE SEQUENCE [MRNA]DEVELOPMENTAL STAGETISSUE SPECIFICITYAltered patterns of sleep and behavioral adaptability in NPAS2-deficient mice.FUNCTIONHistone acetyltransferase-dependent chromatin remodeling and the vascular clock.INTERACTION WITH EP300INDUCTIONCO-dependent activity-controlling mechanism of heme-containing CO-sensor protein, neuronal PAS domain protein 2.HEME-BINDINGRESONANCE RAMAN SPECTROSCOPYACTIVITY REGULATIONPost-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES.INTERACTION WITH BMAL1FUNCTIONPHOSPHORYLATIONSUBCELLULAR LOCATIONNPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions.FUNCTIONDISRUPTION PHENOTYPECLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock.FUNCTIONDISRUPTION PHENOTYPETISSUE SPECIFICITYEffects of mutations in the heme domain on the transcriptional activity and DNA-binding activity of NPAS2.FUNCTIONDNA-BINDINGMUTAGENESIS OF HIS-119 AND HIS-171Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood.FUNCTIONOscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system.REVIEWEvidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators.FUNCTIONNPAS2 deletion impairs responses to restricted feeding but not to metabolic challenges.FUNCTIONDISRUPTION PHENOTYPEEffects of the bHLH domain on axial coordination of heme in the PAS-A domain of neuronal PAS domain protein 2 (NPAS2): conversion from His119/Cys170 coordination to His119/His171 coordination.HEME-BINDINGRESONANCE RAMAN SPECTROSCOPYEffects of NAD(P)H and its derivatives on the DNA-binding activity of NPAS2, a mammalian circadian transcription factor.DNA-BINDINGACTIVITY REGULATIONCircadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells.FUNCTIONDISRUPTION PHENOTYPETISSUE SPECIFICITYINDUCTIONDysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model.FUNCTIONDISRUPTION PHENOTYPESmall heterodimer partner/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism.FUNCTIONNPAS2 regulation of anxiety-like behavior and GABAA receptors.FUNCTIONDISRUPTION PHENOTYPEINDUCTIONTranscriptional 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, BMAL1, 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 BMAL1 or 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-BMAL1|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 BMAL1 transcription, respectively. The NPAS2-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 (PubMed:25212631). 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 (PubMed:29163035).hemeCarbon monoxide (CO) and the redox state of the cell can modulate the transcriptional activity of the NPAS2-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.Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or 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 BMAL1 and this heterodimerization is required for E-box-dependent transactivation. Interacts with EP300.NucleusExpressed in the retinal ganglion cells (at protein level). Expressed in the hypothalamic suprachiasmatic nuclei (SCN) of the brain. Also found in spinal cord, and to a lesser extent in colon, small intestine and uterus. Exhibits a diurnal variation in its expression in the brain (PubMed:29163035).First detected 3 days after birth.Expression in the retinal ganglion cells and heart oscillates in a circadian manner.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. Null mutant mice and the mice with a conditional knockdown in the ventral striatum show a reduced anxiety-like behavior and a reduced sensitivity to diazepam (PubMed:29163035).ActivatorBiological rhythmsDNA damageDNA-bindingHemeIronMetal-bindingNucleusPhosphoproteinReference proteomeRepeatTranscriptionTranscription regulationheme bFeheme bFeHAHAMDEDEKDRAKRASRNKSEKKRRDQFNVLIKELSSMLPGNTRKMDKTTVLEKVIGFLQKHNEVSAQTEICDIQQDWKPSFLSNEEFTQLMLEALDGFVIVVTTDGSIIYVSDSITPLLGHLPADVMDQNLLNFLPEQEHSEVYKILSSHMLVTDSPSPEFLKSDNDLEFYCHLLRGSLNPKEFPTYEYIKFVGNFRSYNNVPSPSCNGFDNTLSRPCHVPLGKDVCFIATVRLATPQFLKEMCVADEPLEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYNYYHIDDLELLARCHQHLMQFGKGKSCCYRFLTKGQQWIWLQTHYYITYHQWNSKPEFIVCTHSVVSYADVRVERRQELALEDPPTEAMHPSAVKEKDSSLEPPQPFNALDMGASGLPSSPSPSASSRSSHKSSHTAMSEPTSTPTKLMAENSTTALPRPATLPQELPVQGLSQAATMPTALHSSASCDLTKQLLLQSLPQTGLQSPPAPVTQFSAQFSMFQTIKDQLEQRTRILQANIRWQQEELHKIQEQLCLVQDSNVQMFLQQPAVSLSFSSTQRPAAQQQLQQRPAAPSQPQLVVNTPLQGQITSTQVTNQHLLRESNVISAQGPKPMRSSQLLPASGRSLSSLPSQFSSTASVLPPGLSLTTIAPTPQDDSQCQPSPDFGHDRQLRLLLSQPIQPMMPGSCDARQPSEVSRTGRQVKYAQSQVMFPSPDSHPTNSSASTPVLLMGQAVLHPSFPASRPSPLQPAQAQQQPPPYLQAPTSLHSEQPDSLLLSTFSQQPGTLGYAATQSTPPQPPRPSRRVSRLSES
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