InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: NPAS2

Summary

InnateDB Protein

IDBP-63635.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

NPAS2

Protein Name

neuronal PAS domain protein 2

Synonyms

bHLHe9; MOP4; PASD4;

Species

Homo sapiens

Ensembl Protein

ENSP00000338283

InnateDB Gene

IDBG-63633 (NPAS2)

Protein Structure

UniProt Annotation

Function

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 CLOCKNPAS2-ARNTL/BMAL1ARNTL2/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. {ECO:0000269PubMed:11441146, ECO:0000269PubMed:11441147, ECO:0000269PubMed:14645221, ECO:0000269PubMed:18439826, ECO:0000269PubMed:18819933}.

Subcellular Localization

Nucleus {ECO:0000255PROSITE- ProRule:PRU00981, ECO:0000269PubMed:14645221}.

Disease Associations

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 30 experimentally validated interaction(s) in this database.

Experimentally validated
Total	30 [view]
Protein-Protein	29 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001047	core promoter binding
GO:0003677	DNA binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0004871	signal transducer activity
GO:0005515	protein binding
GO:0046872	metal ion binding
GO:0046983	protein dimerization activity
GO:0051879	Hsp90 protein binding

Biological Process

GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006974	cellular response to DNA damage stimulus
GO:0007165	signal transduction
GO:0007417	central nervous system development
GO:0032922	circadian regulation of gene expression
GO:0042745	circadian sleep/wake cycle
GO:0044255	cellular lipid metabolic process
GO:0044281	small molecule metabolic process
GO:0045475	locomotor rhythm
GO:0045739	positive regulation of DNA repair
GO:0045893	positive regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0051775	response to redox state
GO:0060548	negative regulation of cell death
GO:2001020	regulation of response to DNA damage stimulus

Cellular Component

GO:0005634	nucleus
GO:0005667	transcription factor complex
GO:0005737	cytoplasm
GO:0005829	cytosol

Protein Structure and Domains

PDB ID

InterPro

IPR000014 PAS domain
IPR001067 Nuclear translocator
IPR001610 PAC motif
IPR011598 Myc-type, basic helix-loop-helix (bHLH) domain
IPR013655 PAS fold-3
IPR013767 PAS fold

PFAM

PF13188
PF13426
PF00010
PF08447
PF00989

PRINTS

PR00785

PIRSF

SMART

SM00091
SM00086
SM00353

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt