InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PER2

Summary

InnateDB Protein

IDBP-84522.6

Last Modified

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

Gene Symbol

PER2

Protein Name

period homolog 2 (Drosophila)

Synonyms

FASPS; FASPS1;

Species

Homo sapiens

Ensembl Protein

ENSP00000254657

InnateDB Gene

IDBG-84518 (PER2)

Protein Structure

UniProt Annotation

Function

Transcriptional repressor 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 syndrome 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. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK:ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK:ARTNL/BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like ARNTL or G6PC. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.

Subcellular Localization

Isoform 1: Nucleus. Cytoplasm {ECO:0000250}. Cytoplasm, perinuclear region {ECO:0000250}. Note=Nucleocytoplasmic shuttling is effected by interaction with other circadian core oscillator proteins and/or by phosphorylation. Translocate to the nucleus after phosphorylation by CSNK1D or CSNK1E. Also translocated to the nucleus by CRY1 or CRY2. PML regulates its nuclear localization.Isoform 2: Nucleus, nucleolus {ECO:0000269PubMed:24202686}.

Disease Associations

Advanced sleep phase syndrome, familial, 1 (FASPS1) [MIM:604348]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269PubMed:11232563}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level). {ECO:0000269PubMed:9427249}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 16 experimentally validated interaction(s) in this database.
They are also associated with 28 interaction(s) predicted by orthology.

Experimentally validated
Total	16 [view]
Protein-Protein	12 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	3 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	28 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000976	transcription regulatory region sequence-specific DNA binding
GO:0000989	transcription factor binding transcription factor activity
GO:0001222	transcription corepressor binding
GO:0003713	transcription coactivator activity
GO:0004871	signal transducer activity
GO:0005515	protein binding
GO:0008134	transcription factor binding
GO:0019900	kinase binding
GO:0035257	nuclear hormone receptor binding
GO:0036002	pre-mRNA binding
GO:0042826	histone deacetylase binding
GO:0043130	ubiquitin binding
GO:0070063	RNA polymerase binding
GO:1990226	histone methyltransferase binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0002931	response to ischemia
GO:0005978	glycogen biosynthetic process
GO:0006094	gluconeogenesis
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006631	fatty acid metabolic process
GO:0007165	signal transduction
GO:0007623	circadian rhythm
GO:0019229	regulation of vasoconstriction
GO:0019249	lactate biosynthetic process
GO:0031397	negative regulation of protein ubiquitination
GO:0032922	circadian regulation of gene expression
GO:0042752	regulation of circadian rhythm
GO:0042754	negative regulation of circadian rhythm
GO:0045892	negative regulation of transcription, DNA-templated
GO:0050767	regulation of neurogenesis
GO:0050796	regulation of insulin secretion
GO:0050872	white fat cell differentiation
GO:0051726	regulation of cell cycle
GO:0051946	regulation of glutamate uptake involved in transmission of nerve impulse
GO:0060567	negative regulation of DNA-templated transcription, termination
GO:0070345	negative regulation of fat cell proliferation
GO:0070932	histone H3 deacetylation
GO:0097167	circadian regulation of translation
GO:2000678	negative regulation of transcription regulatory region DNA binding