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Q9Z301 (PER2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 101. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Period circadian protein homolog 2

Short name=rPER2
Alternative name(s):
Circadian clock protein PERIOD 2
Gene names
Name:Per2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length1257 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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 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. 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 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. Ref.5

Subunit structure

Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with of the CLOCK-ARNTL/BMAL1 (off DNA). Interacts with ARNTL2/BMAL2. Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interacts, via its second PAS domain, with TIMELESS in vitro. Interacts with NFIL3. Different large complexes have been identified with different repressive functions. The core of PER complexes is composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or CSNK1E. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with SETX; the interaction inhibits termination of circadian target genes. Interacts with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and THRA; the interaction with at least PPARG is ligand dependent. Interacts with PML. Ref.2 Ref.3 Ref.7

Subcellular location

Nucleus. Cytoplasm. Cytoplasmperinuclear region By similarity. 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 By similarity. Ref.3

Tissue specificity

Expressed in all tissues examined including eye, brain, heart, lung, spleen, liver, pancreas and kidney. In the CNS, highly expressed in the SCN, internal granular layer of granular cells of the olfactory bulb, tuberculum olfactorium, piriform cortex, gyrus dentatus of the hippocampus, cerebellum, pars tuberalis/median eminence, and pituitary, and moderately in the tenia tecta, caudate putamen, accumbens nucleus, superior and inferior colliculus and pineal gland. Ref.1 Ref.4 Ref.6

Induction

In eye, brain, heart, lung, spleen, liver, pancreas and kidney, expression exhibits a circadian rhythm in the presence of light/dark cycles. Ref.1 Ref.6

Post-translational modification

Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1 By similarity.

Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibit by CRY1 By similarity.

Sequence similarities

Contains 1 PAC (PAS-associated C-terminal) domain.

Contains 2 PAS (PER-ARNT-SIM) domains.

Ontologies

Keywords
   Biological processBiological rhythms
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   DomainRepeat
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcircadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

circadian regulation of translation

Inferred from sequence or structural similarity. Source: UniProtKB

circadian rhythm

Inferred from expression pattern Ref.6. Source: UniProtKB

fatty acid metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

gluconeogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

glycogen biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

histone H3 deacetylation

Inferred from sequence or structural similarity. Source: UniProtKB

lactate biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of fat cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 12397359Ref.5PubMed 15147242. Source: BHF-UCL

negative regulation of transcription regulatory region DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of glutamate uptake involved in transmission of nerve impulse

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of insulin secretion

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of neurogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of vasoconstriction

Inferred from sequence or structural similarity. Source: UniProtKB

response to ischemia

Inferred from sequence or structural similarity. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

white fat cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentnucleus

Inferred from direct assay Ref.3. Source: RGD

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionprotein binding

Inferred from physical interaction Ref.2Ref.7. Source: UniProtKB

signal transducer activity

Inferred from electronic annotation. Source: InterPro

transcription coactivator activity

Inferred from sequence or structural similarity. Source: UniProtKB

transcription factor binding transcription factor activity

Inferred from direct assay PubMed 15147242. Source: BHF-UCL

transcription regulatory region sequence-specific DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12571257Period circadian protein homolog 2
PRO_0000162632

Regions

Domain179 – 24668PAS 1
Domain319 – 38567PAS 2
Domain393 – 43644PAC
Region478 – 4825Important for protein stability
Region555 – 763209CSNK1E binding domain
Region882 – 1067186Interaction with PPARG By similarity
Region1157 – 1257101CRY binding domain
Motif109 – 11810Nuclear export signal 1 By similarity
Motif306 – 3105LXXLL
Motif460 – 46910Nuclear export signal 3 By similarity
Motif778 – 79417Nuclear localization signal Ref.3
Motif983 – 9908Nuclear export signal 2 By similarity
Motif1051 – 10555LXXLL
Compositional bias831 – 961131Pro-rich
Compositional bias1033 – 111179Ser-rich

Amino acid modifications

Modified residue5251Phosphoserine By similarity
Modified residue5281Phosphoserine By similarity
Modified residue5311Phosphoserine By similarity
Modified residue5381Phosphoserine By similarity
Modified residue5441Phosphoserine By similarity
Modified residue5541Phosphothreonine By similarity
Modified residue6591Phosphoserine By similarity
Modified residue6931Phosphoserine By similarity
Modified residue6971Phosphoserine By similarity
Modified residue7061Phosphoserine By similarity
Modified residue7581Phosphoserine By similarity
Modified residue7631Phosphoserine By similarity
Modified residue8581Phosphothreonine By similarity
Modified residue9391Phosphoserine By similarity
Modified residue9641Phosphothreonine By similarity
Modified residue9711Phosphoserine By similarity
Modified residue11261Phosphoserine By similarity

Experimental info

Mutagenesis93 – 975SGCSS → IGCSI: No effect on interaction with BTRC and FBXW11. Strongly decreases interaction with BTRC and FBXW11 and increases protein stability; when associated with 478-N--N-482. Ref.7
Mutagenesis478 – 4825SGYGS → NGYGN: Strongly decreases interaction with BTRC and FBXW11 and increases protein stability. Strongly decreases interaction with BTRC and FBXW11 and increases protein stability; when associated with 93-I--I-97. Ref.7

Sequences

Sequence LengthMass (Da)Tools
Q9Z301 [UniParc].

Last modified May 1, 1999. Version 1.
Checksum: A772E3C453E63CED

FASTA1,257136,028
        10         20         30         40         50         60 
MNGYVDFSPS PTSPTQEPGE PQPTQAVLQE DVDMSSGSSG NENCSTGRDS QGSDCDDSGK 

        70         80         90        100        110        120 
ELRMLVESSN THPSPDDTFR LMMTEAEHNP STSGCSSEQS AKADAHKELI RTLRELKVHL 

       130        140        150        160        170        180 
PADKKAKGKA STLATLKYAL RSVKQVKANE EYYQLLMSSE SQPCSVDVPS YTMEQVEGIT 

       190        200        210        220        230        240 
SEYIVKNSDM FAVAVSLVSG KILYISNQVA PIFHCKKDAF SDAKFVEFLA PHDVSVFHSY 

       250        260        270        280        290        300 
TTPYKLPPWS VSSGLDSFTQ ECMEEKSFFC RVSVGKHHEN EIRYQPFRMT PYLVKVQEQK 

       310        320        330        340        350        360 
GAASQLCCLL LAERVHSGYE APRIPPEKRI FTTTHTPNCL FQDVDERAVP LLGYLPQDLI 

       370        380        390        400        410        420 
ETPVLVQLHP SDRPLMLAIH KKILQASGQP FDYSPIRFRT RNGEYITLDT SWSSFINPWS 

       430        440        450        460        470        480 
RKISFIIGRH KVRVGPLNED VFAASPCPEE KTPHPSVQEL TEQIHRLLMQ PVPHSGSSGY 

       490        500        510        520        530        540 
GSLGSNGSHE HLMSQTSSSD SNGQEESHWR RSGIFKTSGK SQSKSHFSPE SGGQKEASVA 

       550        560        570        580        590        600 
EMQSSPPAQV RSVTTMERDS SGASLPKASF PEELTYKSQP PCSYQQISCL DSVIRYLESC 

       610        620        630        640        650        660 
NEAATLKRKC EFPANIPSRK ATVSPGLHSG EAARSSKVTS HTEVSAHLSS LALPGKAESV 

       670        680        690        700        710        720 
VSLTSQCSYS STIVHVGDKK PQPELETVED VASGPESQDD AAGGLSQEKG SLQKLGLTKE 

       730        740        750        760        770        780 
VLAAHTQREE QGFLQRFREV SRLGALQAHC QNYLQERSRA PASDRGLRNA SGIESSWKKT 

       790        800        810        820        830        840 
GKNRKLKSKR VKTRDSSEST GSGGPVSHRP PLVGLNATAW SPSDTSQSSC PSAPFPAPVP 

       850        860        870        880        890        900 
AYPLPVFPAP GIVSTPGTVV APPAAAHTGF TMPVVPMGTQ PEFAVQPLPF AAPLAPVMAF 

       910        920        930        940        950        960 
MLPSYPFPPA TPNLPQAFFP SQPHFPAHPT LASEITPASQ AEFPSRTSML RQPCACPVTP 

       970        980        990       1000       1010       1020 
PAGTVALGRA SPPLFQSRGS SPLQLNLLQL EEAPESSTGA AGTLGTTGTA ASGLDCTSGA 

      1030       1040       1050       1060       1070       1080 
SRDRQPKAPP TCSEPSDTQN SDAISTSSDL LNLLLGEDLC SATGSALSRS GASATSDSLG 

      1090       1100       1110       1120       1130       1140 
SSSLGCDTSR SGAGSSDTSH TSKYFGSIDS SENNHKAKMI TDTEESEQFI KYVLQDPIWL 

      1150       1160       1170       1180       1190       1200 
LMANTDDNIM MTYQLPSRDL QAVLKEDQEK LKLLQRSQPH FTEGQRRELR EVHPWVHTGG 

      1210       1220       1230       1240       1250 
LPTAIDVTGC VYCESEEKGN LCLPYEEDSP SLGLCDTSEA KEEESGQLAN PRKEAQT 

« Hide

References

[1]"Multitissue circadian expression of rat period homologue (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain."
Sakamoto K., Nagase T., Fukui H., Horikawa K., Okada T., Tanaka H., Sato K., Miyake Y., Ohara O., Kako K., Ishida N.
J. Biol. Chem. 273:27039-27042(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INDUCTION.
Strain: Sprague-Dawley.
Tissue: Brain.
[2]"Molecular characterization and nuclear localization of rat timeless-like gene product."
Sakamoto S., Miyazaki K., Fukui H., Oishi K., Hayasaka N., Okada M., Kamakura M., Taniguchi T., Nagai K., Ishida N.
Biochem. Biophys. Res. Commun. 279:131-138(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TIMELESS.
[3]"Nuclear entry mechanism of rat PER2 (rPER2): role of rPER2 in nuclear localization of CRY protein."
Miyazaki K., Mesaki M., Ishida N.
Mol. Cell. Biol. 21:6651-6659(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CRY1, CRY BINDING DOMAIN, NUCLEAR LOCALIZATION SIGNAL, SUBCELLULAR LOCATION.
[4]"Distribution of the rhythm-related genes rPERIOD1, rPERIOD2, and rCLOCK, in the rat brain."
Shieh K.-R.
Neuroscience 118:831-843(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[5]"A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation."
Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R., Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I., Kato Y.
Biochem. Biophys. Res. Commun. 313:117-124(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Indication of circadian oscillations in the rat pancreas."
Muehlbauer E., Wolgast S., Finckh U., Peschke D., Peschke E.
FEBS Lett. 564:91-96(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, INDUCTION.
[7]"The role of {beta}-TrCP1 and {beta}-TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2."
Ohsaki K., Oishi K., Kozono Y., Nakayama K., Nakayama K.I., Ishida N.
J. Biochem. 144:609-618(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BTRC AND FBXW11, MUTAGENESIS OF 93-SER--SER-97 AND 478-SER--SER-482.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB016532 mRNA. Translation: BAA34187.1.
PIRT13957.
RefSeqNP_113866.1. NM_031678.1.
XP_006245538.1. XM_006245476.1.
XP_006245539.1. XM_006245477.1.
UniGeneRn.25935.

3D structure databases

ProteinModelPortalQ9Z301.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid248899. 2 interactions.
STRING10116.ENSRNOP00000027507.

Proteomic databases

PaxDbQ9Z301.
PRIDEQ9Z301.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000027506; ENSRNOP00000027507; ENSRNOG00000020254.
GeneID63840.
KEGGrno:63840.

Organism-specific databases

CTD8864.
RGD61945. Per2.

Phylogenomic databases

eggNOGNOG253593.
GeneTreeENSGT00510000046467.
HOGENOMHOG000231111.
HOVERGENHBG008167.
InParanoidQ9Z301.
KOK02633.
OMANATAWSP.
OrthoDBEOG78SQH2.
PhylomeDBQ9Z301.
TreeFamTF318445.

Gene expression databases

GenevestigatorQ9Z301.

Family and domain databases

InterProIPR001610. PAC.
IPR000014. PAS.
IPR013655. PAS_fold_3.
IPR022728. Period_circadian-like_C.
[Graphical view]
PfamPF08447. PAS_3. 1 hit.
PF12114. Period_C. 1 hit.
[Graphical view]
SMARTSM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMSSF55785. SSF55785. 1 hit.
PROSITEPS50112. PAS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio612434.
PROQ9Z301.

Entry information

Entry namePER2_RAT
AccessionPrimary (citable) accession number: Q9Z301
Entry history
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: May 1, 1999
Last modified: July 9, 2014
This is version 101 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families