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Protein

Period circadian protein homolog 2

Gene

Per2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 NR1D1/2 and RORA/B/G, 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 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.17 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processBiological rhythms, Transcription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Period circadian protein homolog 2
Short name:
mPER2
Alternative name(s):
Circadian clock protein PERIOD 2
Gene namesi
Name:Per2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1195265 Per2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Animals show severely disrupted circadian behavior. During myocardial ischemia, they have larger infarct sizes with deficient lactate production. Mice show reduced muscle strength under stress conditions, show endothelial dysfunctions and have a mean arterial pressure significantly lower compared to wild types. They have elevated circulatory insulin levels associated with enhanced glucose-stimulated insulin secretion and impaired insulin clearance. Animals also have increased levels of liver glycogen and impaired hepatic gluconeogenesis. They display altered lipid metabolism with drastic reduction of total triacylglycerides and non-esterified fatty acids. Double knockouts for PER2 and PER1 show an abrupt loss of rhythmicity immediately upon transfer to exposure to constant darkness. Animals have largely affected the water intake (polydipsia) and urine volume (polyuria). Double knocknouts for PER2 and PER3 show the same phenotype as PER2 simple knockouts. Double knockout for NR1D1 and PER2 show a significantly shorter period length compared with wild type or single knockouts for both genes. 50% of double knockouts animals show a stable circadian throughout at least 5 weeks in constant darkness. The other 50% of animals lose their circadian rhythmicity when held in constant darkness for an average of 21 days. Animals have blunted steady-state levels of glycogen in the liver in spite of normal patterns of food consumption.8 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi113 – 116LKEL → AKEA: Accumulates in the nucleus. Exlcusively nuclear; when associated with 464-A--A-467 and 985-A--A-990. 1 Publication4
Mutagenesisi306 – 310LCCLL → ACCAA: Abolishes interaction with PPARA and NR1D1. No effect on interaction with CRY1. Abolishes interaction with PPARA and NR1D1 as well as reduces the amplitude of ARNTL expression; when associated with 1052-E--A-1055. 1 Publication5
Mutagenesisi306 – 310Missing : Abolishes interaction with NR1D1. 1 Publication5
Mutagenesisi415F → E: Abolishes dimerization. 1 Publication1
Mutagenesisi419W → E: Abolishes dimerization. 1 Publication1
Mutagenesisi427I → E: Abolishes dimerization. 1 Publication1
Mutagenesisi464 – 467IHRL → AHRA: Accumulates in the nucleus. Exlcusively nuclear; when associated with 113-A--A-116 and 985-A--A-990. 1 Publication4
Mutagenesisi985 – 990LNLLQL → ANAAQA: Slightly accumulates in the nucleus. Exlcusively nuclear; when associated with 464-A--A-467 and 985-A--A-990. 1 Publication6
Mutagenesisi1052 – 1055NLLL → EAAA: No effect on interaction with PPARA. Abolishes interaction with PPARA and NR1D1 as well as reduces the amplitude of ARNTL expression; when associated with 306-A--A-310. 1 Publication4
Mutagenesisi1052 – 1055Missing : No effect on interaction with NR1D1. 1 Publication4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001626311 – 1257Period circadian protein homolog 2Add BLAST1257

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei525Phosphoserine1 Publication1
Modified residuei528Phosphoserine1 Publication1
Modified residuei531Phosphoserine1 Publication1
Modified residuei538Phosphoserine1 Publication1
Modified residuei544Phosphoserine1 Publication1
Modified residuei554Phosphothreonine1 Publication1
Modified residuei659PhosphoserineBy similarity1
Modified residuei693PhosphoserineCombined sources1
Modified residuei697PhosphoserineCombined sources1
Modified residuei706Phosphoserine1 Publication1
Modified residuei758Phosphoserine1 Publication1
Modified residuei763Phosphoserine1 Publication1
Modified residuei858Phosphothreonine1 Publication1
Modified residuei939Phosphoserine1 Publication1
Modified residuei964Phosphothreonine1 Publication1
Modified residuei971Phosphoserine1 Publication1
Modified residuei1126Phosphoserine1 Publication1

Post-translational modificationi

Acetylated. Deacetylated by SIRT1, resulting in decreased protein stability.1 Publication
Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1.5 Publications
Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibited by CRY1.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiO54943
PRIDEiO54943

PTM databases

iPTMnetiO54943
PhosphoSitePlusiO54943

Expressioni

Tissue specificityi

In the brain, high expression in SCN during the subjective day. Constitutive expression in the cornu ammonis and in the dentate gyrus of the hyppocampus. Also expressed in the piriform cortex and the glomeruli of the olfactory bulb, and at a lower extent in the cerebral cortex. Not expressed in the pars tuberalis and the Purkinje neurons. Also expressed in adipose tissue (white and brown), heart, kidney, bladder, lumbar spinal cord, skeletal muscle, spleen, lung, pancreas and liver with highest levels in skeletal muscle and liver and lowest levels in spleen.7 Publications

Developmental stagei

Expressed in the SCN during late fetal and early neonatal life. Expression increases during adipogenesis.2 Publications

Inductioni

Oscillates diurnally in several tissues, mainly in central nervous system and liver (at protein levels) but also in pancreas, bladder and lumbar spinal cord. Rhythmic levels are critical for the generation of circadian rhythms in central as well as peripheral clocks. Targeted degradation of PER and CRY proteins enables the reactivation of CLOCK-ARTNL/BMAL1, thus initiating a new circadian transcriptional cycle with an intrinsic period of 24 hours.7 Publications

Gene expression databases

CleanExiMM_PER2

Interactioni

Subunit structurei

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 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. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO and SFPQ. Interacts with SIRT1. Interacts with CAVIN3. Interacts with MAGEL2.25 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi202112, 25 interactors
ComplexPortaliCPX-3209 Cry1-Per2 complex
CPX-3210 Cry2-Per2 complex
DIPiDIP-38518N
ELMiO54943
IntActiO54943, 32 interactors
MINTiO54943
STRINGi10090.ENSMUSP00000066620

Structurei

Secondary structure

11257
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO54943
SMRiO54943
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO54943

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini179 – 246PAS 1PROSITE-ProRule annotationAdd BLAST68
Domaini319 – 385PAS 2PROSITE-ProRule annotationAdd BLAST67
Domaini393 – 436PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni478 – 482Important for protein stabilityBy similarity5
Regioni510 – 709CSNK1E binding domainAdd BLAST200
Regioni882 – 1067Interaction with PPARG1 PublicationAdd BLAST186
Regioni1157 – 1257CRY binding domainBy similarityAdd BLAST101

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi109 – 118Nuclear export signal 11 Publication10
Motifi306 – 310LXXLL5
Motifi460 – 469Nuclear export signal 21 Publication10
Motifi778 – 794Nuclear localization signal1 PublicationAdd BLAST17
Motifi983 – 990Nuclear export signal 31 Publication8
Motifi1051 – 1055LXXLL5

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi831 – 961Pro-richAdd BLAST131
Compositional biasi1061 – 1111Ser-richAdd BLAST51

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3753 Eukaryota
ENOG410Y118 LUCA
HOVERGENiHBG008167
InParanoidiO54943
KOiK02633
PhylomeDBiO54943
TreeFamiTF318445

Family and domain databases

CDDicd00130 PAS, 1 hit
InterProiView protein in InterPro
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013655 PAS_fold_3
IPR022728 Period_circadian-like_C
PfamiView protein in Pfam
PF08447 PAS_3, 1 hit
PF12114 Period_C, 1 hit
SMARTiView protein in SMART
SM00091 PAS, 2 hits
SUPFAMiSSF55785 SSF55785, 1 hit
PROSITEiView protein in PROSITE
PS50112 PAS, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

O54943-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MNGYVDFSPS PTSPTKEPGA PQPTQAVLQE DVDMSSGSSG NENCSTGRDS
60 70 80 90 100
QGSDCDDNGK ELRMLVESSN THPSPDDAFR LMMTEAEHNP STSGCSSEQS
110 120 130 140 150
AKADAHKELI RTLKELKVHL PADKKAKGKA STLATLKYAL RSVKQVKANE
160 170 180 190 200
EYYQLLMSSE SQPCSVDVPS YSMEQVEGIT SEYIVKNADM FAVAVSLVSG
210 220 230 240 250
KILYISNQVA SIFHCKKDAF SDAKFVEFLA PHDVSVFHSY TTPYKLPPWS
260 270 280 290 300
VCSGLDSFTQ ECMEEKSFFC RVSVGKHHEN EIRYQPFRMT PYLVKVQEQQ
310 320 330 340 350
GAESQLCCLL LAERVHSGYE APRIPPEKRI FTTTHTPNCL FQAVDERAVP
360 370 380 390 400
LLGYLPQDLI ETPVLVQLHP SDRPLMLAIH KKILQAGGQP FDYSPIRFRT
410 420 430 440 450
RNGEYITLDT SWSSFINPWS RKISFIIGRH KVRVGPLNED VFAAPPCPEE
460 470 480 490 500
KTPHPSVQEL TEQIHRLLMQ PVPHSGSSGY GSLGSNGSHE HLMSQTSSSD
510 520 530 540 550
SNGQEESHRR RSGIFKTSGK IQTKSHVSHE SGGQKEASVA EMQSSPPAQV
560 570 580 590 600
KAVTTIERDS SGASLPKASF PEELAYKNQP PCSYQQISCL DSVIRYLESC
610 620 630 640 650
SEAATLKRKC EFPANIPSRK ATVSPGLHSG EAARPSKVTS HTEVSAHLSS
660 670 680 690 700
LTLPGKAESV VSLTSQCSYS STIVHVGDKK PQPELETVED MASGPESLDG
710 720 730 740 750
AAGGLSQEKG PLQKLGLTKE VLAAHTQKEE QGFLQRFREV SRLSALQAHC
760 770 780 790 800
QNYLQERSRA QASDRGLRNT SGLESSWKKT GKNRKLKSKR VKTRDSSEST
810 820 830 840 850
GSGGPVSHRP PLMGLNATAW SPSDTSQSSC PSAPFPTAVP AYPLPVFQAP
860 870 880 890 900
GIVSTPGTVV APPAATHTGF TMPVVPMGTQ PEFAVQPLPF AAPLAPVMAF
910 920 930 940 950
MLPSYPFPPA TPNLPQAFLP SQPHFPAHPT LASEITPASQ AEFPSRTSTL
960 970 980 990 1000
RQPCACPVTP PAGTVALGRA SPPLFQSRGS SPLQLNLLQL EEAPEGSTGA
1010 1020 1030 1040 1050
AGTLGTTGTA ASGLDCTSGT SRDRQPKAPP TCNEPSDTQN SDAISTSSDL
1060 1070 1080 1090 1100
LNLLLGEDLC SATGSALSRS GASATSDSLG SSSLGFGTSQ SGAGSSDTSH
1110 1120 1130 1140 1150
TSKYFGSIDS SENNHKAKMI PDTEESEQFI KYVLQDPIWL LMANTDDSIM
1160 1170 1180 1190 1200
MTYQLPSRDL QAVLKEDQEK LKLLQRSQPR FTEGQRRELR EVHPWVHTGG
1210 1220 1230 1240 1250
LPTAIDVTGC VYCESEEKGN ICLPYEEDSP SPGLCDTSEA KEEEGEQLTG

PRIEAQT
Length:1,257
Mass (Da):135,881
Last modified:July 15, 1999 - v3
Checksum:i554B8AFF036CF7FB
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0R4J0U3A0A0R4J0U3_MOUSE
Period circadian protein homolog 2
Per2
1,257Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti445P → S in AAC53592 (PubMed:9427249).Curated1
Sequence conflicti728K → R in AAC53592 (PubMed:9427249).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF036893 mRNA Translation: AAC39942.1
AF035830 mRNA Translation: AAC53592.1
CCDSiCCDS35663.1
PIRiT09493
RefSeqiNP_035196.2, NM_011066.3
UniGeneiMm.482463

Genome annotation databases

GeneIDi18627
KEGGimmu:18627

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF036893 mRNA Translation: AAC39942.1
AF035830 mRNA Translation: AAC53592.1
CCDSiCCDS35663.1
PIRiT09493
RefSeqiNP_035196.2, NM_011066.3
UniGeneiMm.482463

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3GDIX-ray2.40A/B170-473[»]
4CT0X-ray2.45B1132-1252[»]
4U8HX-ray2.80B/D1095-1215[»]
ProteinModelPortaliO54943
SMRiO54943
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi202112, 25 interactors
ComplexPortaliCPX-3209 Cry1-Per2 complex
CPX-3210 Cry2-Per2 complex
DIPiDIP-38518N
ELMiO54943
IntActiO54943, 32 interactors
MINTiO54943
STRINGi10090.ENSMUSP00000066620

PTM databases

iPTMnetiO54943
PhosphoSitePlusiO54943

Proteomic databases

PaxDbiO54943
PRIDEiO54943

Protocols and materials databases

DNASUi18627
Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi18627
KEGGimmu:18627

Organism-specific databases

CTDi8864
MGIiMGI:1195265 Per2

Phylogenomic databases

eggNOGiKOG3753 Eukaryota
ENOG410Y118 LUCA
HOVERGENiHBG008167
InParanoidiO54943
KOiK02633
PhylomeDBiO54943
TreeFamiTF318445

Miscellaneous databases

ChiTaRSiPer2 mouse
EvolutionaryTraceiO54943
PROiPR:O54943
SOURCEiSearch...

Gene expression databases

CleanExiMM_PER2

Family and domain databases

CDDicd00130 PAS, 1 hit
InterProiView protein in InterPro
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013655 PAS_fold_3
IPR022728 Period_circadian-like_C
PfamiView protein in Pfam
PF08447 PAS_3, 1 hit
PF12114 Period_C, 1 hit
SMARTiView protein in SMART
SM00091 PAS, 2 hits
SUPFAMiSSF55785 SSF55785, 1 hit
PROSITEiView protein in PROSITE
PS50112 PAS, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiPER2_MOUSE
AccessioniPrimary (citable) accession number: O54943
Secondary accession number(s): O54954
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 15, 1999
Last modified: November 7, 2018
This is version 151 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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