PER2_SPAJD
ID PER2_SPAJD Reviewed; 1248 AA.
AC Q8K3T2;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 25-MAY-2022, entry version 82.
DE RecName: Full=Period circadian protein homolog 2;
DE Short=sPER2;
DE AltName: Full=Circadian clock protein PERIOD 2;
GN Name=PER2;
OS Spalax judaei (Judean Mountains blind mole rat) (Nannospalax judaei).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Spalacidae; Spalacinae; Nannospalax.
OX NCBI_TaxID=134510;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION.
RC TISSUE=Brain;
RX PubMed=12193657; DOI=10.1073/pnas.182423299;
RA Avivi A., Oster H., Joel A., Albrecht U., Nevo E.;
RT "Circadian genes in a blind subterranean mammal II: conservation and
RT uniqueness of the three Period homologs in the blind subterranean mole rat,
RT Spalax ehrenbergi superspecies.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:11718-11723(2002).
CC -!- FUNCTION: Transcriptional repressor which forms a core component of the
CC circadian clock. The circadian clock, an internal time-keeping system,
CC regulates various physiological processes through the generation of
CC approximately 24 hour circadian rhythms in gene expression, which are
CC translated into rhythms in metabolism and behavior. It is derived from
CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an
CC important regulator of a wide array of physiological functions
CC including metabolism, sleep, body temperature, blood pressure,
CC endocrine, immune, cardiovascular, and renal function. Consists of two
CC major components: the central clock, residing in the suprachiasmatic
CC nucleus (SCN) of the brain, and the peripheral clocks that are present
CC in nearly every tissue and organ system. Both the central and
CC peripheral clocks can be reset by environmental cues, also known as
CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the
CC central clock is light, which is sensed by retina and signals directly
CC to the SCN. The central clock entrains the peripheral clocks through
CC neuronal and hormonal signals, body temperature and feeding-related
CC cues, aligning all clocks with the external light/dark cycle. Circadian
CC rhythms allow an organism to achieve temporal homeostasis with its
CC environment at the molecular level by regulating gene expression to
CC create a peak of protein expression once every 24 hours to control when
CC a particular physiological process is most active with respect to the
CC solar day. Transcription and translation of core clock components
CC (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and
CC CRY2) plays a critical role in rhythm generation, whereas delays
CC imposed by post-translational modifications (PTMs) are important for
CC determining the period (tau) of the rhythms (tau refers to the period
CC of a rhythm and is the length, in time, of one complete cycle). A
CC diurnal rhythm is synchronized with the day/night cycle, while the
CC ultradian and infradian rhythms have a period shorter and longer than
CC 24 hours, respectively. Disruptions in the circadian rhythms contribute
CC to the pathology of cardiovascular diseases, cancer, metabolic syndrome
CC and aging. A transcription/translation feedback loop (TTFL) forms the
CC core of the molecular circadian clock mechanism. Transcription factors,
CC CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb
CC of the feedback loop, act in the form of a heterodimer and activate the
CC transcription of core clock genes and clock-controlled genes (involved
CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3')
CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which
CC are transcriptional repressors form the negative limb of the feedback
CC loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2
CC heterodimer inhibiting its activity and thereby negatively regulating
CC their own expression. This heterodimer also activates nuclear receptors
CC NR1D1/2 and RORA/B/G, which form a second feedback loop and which
CC activate and repress ARNTL/BMAL1 transcription, respectively. PER1 and
CC PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate
CC circadian timing, but also contribute directly to repression of clock-
CC controlled target genes through interaction with several classes of
CC RNA-binding proteins, helicases and others transcriptional repressors.
CC PER appears to regulate circadian control of transcription by at least
CC three different modes. First, interacts directly with the CLOCK-
CC ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit
CC complexes containing the SIN3-HDAC that remodel chromatin to repress
CC transcription. Second, brings H3K9 methyltransferases such as SUV39H1
CC and SUV39H2 to the E-box elements of the circadian target genes, like
CC PER2 itself or PER1. The recruitment of each repressive modifier to the
CC DNA seems to be very precisely temporally orchestrated by the large PER
CC complex, the deacetylases acting before than the methyltransferases.
CC Additionally, large PER complexes are also recruited to the target
CC genes 3' termination site through interactions with RNA-binding
CC proteins and helicases that may play a role in transcription
CC termination to regulate transcription independently of CLOCK-
CC ARTNL/BMAL1 interactions. Recruitment of large PER complexes to the
CC elongating polymerase at PER and CRY termination sites inhibited SETX
CC action, impeding RNA polymerase II release and thereby repressing
CC transcriptional reinitiation. May propagate clock information to
CC metabolic pathways via the interaction with nuclear receptors.
CC Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at
CC the promoter of nuclear receptors target genes like ARNTL or G6PC1.
CC Directly and specifically represses PPARG proadipogenic activity by
CC blocking PPARG recruitment to target promoters and thereby
CC transcriptional activation. Required for fatty acid and lipid
CC metabolism, is involved as well in the regulation of circulating
CC insulin levels. Plays an important role in the maintenance of
CC cardiovascular functions through the regulation of NO and
CC vasodilatatory prostaglandins production in aortas. Controls circadian
CC glutamate uptake in synaptic vesicles through the regulation of VGLUT1
CC expression. May also be involved in the regulation of inflammatory
CC processes. Represses the CLOCK-ARNTL/BMAL1 induced transcription of
CC BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the
CC TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.
CC {ECO:0000250|UniProtKB:O54943}.
CC -!- SUBUNIT: Homodimer. Component of the circadian core oscillator, which
CC includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2,
CC CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with
CC CLOCK-ARNTL/BMAL1 (off DNA). Interacts with ARNTL2/BMAL2. Interacts
CC directly with PER1 and PER3, and through a C-terminal domain, with CRY1
CC and CRY2. Interacts, via its second PAS domain, with TIMELESS in vitro.
CC Interacts with NFIL3. Different large complexes have been identified
CC with different repressive functions. The core of PER complexes is
CC composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or
CC CSNK1E. The large PER complex involved in the repression of
CC transcriptional termination is composed of at least PER2, CDK9, DDX5,
CC DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the
CC histone deacetylation is composed of at least HDAC1, PER2, SFPQ and
CC SIN3A. The large PER complex involved in the histone methylation is
CC composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3
CC mediates the formation of the complex. Interacts with SETX; the
CC interaction inhibits termination of circadian target genes. Interacts
CC with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and
CC THRA; the interaction with at least PPARG is ligand dependent.
CC Interacts with PML. Interacts (phosphorylated) with BTRC and FBXW11;
CC the interactions trigger proteasomal degradation. Interacts with NONO
CC and SFPQ. Interacts with PRKCDBP. Interacts with MAGEL2. Interacts with
CC MAP1LC3B (By similarity). Interacts with HNF4A (By similarity).
CC {ECO:0000250|UniProtKB:O15055, ECO:0000250|UniProtKB:O54943}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:O54943}. Cytoplasm
CC {ECO:0000250|UniProtKB:O54943}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:O54943}. Note=Nucleocytoplasmic shuttling is
CC effected by interaction with other circadian core oscillator proteins
CC and/or by phosphorylation. Translocate to the nucleus after
CC phosphorylation by CSNK1D or CSNK1E. Also translocated to the nucleus
CC by CRY1 or CRY2. PML regulates its nuclear localization (By
CC similarity). {ECO:0000250|UniProtKB:O54943}.
CC -!- TISSUE SPECIFICITY: Expressed in the brain, mainly in the
CC suprachiasmatic nucleus (SCN). Expression also found in the harderian
CC gland, lung, eye, intestine, liver and skeletal muscle.
CC {ECO:0000269|PubMed:12193657}.
CC -!- INDUCTION: Exhibits circadian rhythm expression. In the SCN and
CC harderian gland, maximum levels at ZT12. Maximum levels in the eye and
CC liver at ZT18. Under constant darkness, maximum levels, in SCN and
CC harderian gland, during subjective day at CT12. In the eye, maximum
CC levels at CT18. {ECO:0000269|PubMed:12193657}.
CC -!- PTM: Acetylated. Deacetylated by SIRT1, resulting in decreased protein
CC stability. Deacetylated by SIRT6, preventing its degradation by the
CC proteasome, resulting in increased protein stability.
CC {ECO:0000250|UniProtKB:O54943}.
CC -!- PTM: Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in
CC PER2 protein degradation. May be dephosphorylated by PP1 (By
CC similarity). {ECO:0000250|UniProtKB:O54943}.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation.
CC Ubiquitination may be inhibited by CRY1.
CC {ECO:0000250|UniProtKB:O54943}.
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DR EMBL; AJ345060; CAC95107.1; -; mRNA.
DR AlphaFoldDB; Q8K3T2; -.
DR SMR; Q8K3T2; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0097167; P:circadian regulation of translation; ISS:UniProtKB.
DR GO; GO:0006631; P:fatty acid metabolic process; ISS:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0005978; P:glycogen biosynthetic process; ISS:UniProtKB.
DR GO; GO:0070932; P:histone H3 deacetylation; ISS:UniProtKB.
DR GO; GO:0019249; P:lactate biosynthetic process; ISS:UniProtKB.
DR GO; GO:0042754; P:negative regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0070345; P:negative regulation of fat cell proliferation; ISS:UniProtKB.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:2000678; P:negative regulation of transcription regulatory region DNA binding; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0051946; P:regulation of glutamate uptake involved in transmission of nerve impulse; ISS:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB.
DR GO; GO:0019229; P:regulation of vasoconstriction; ISS:UniProtKB.
DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB.
DR GO; GO:0050872; P:white fat cell differentiation; ISS:UniProtKB.
DR CDD; cd00130; PAS; 1.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013655; PAS_fold_3.
DR InterPro; IPR022728; Period_circadian-like_C.
DR Pfam; PF08447; PAS_3; 1.
DR Pfam; PF12114; Period_C; 1.
DR SUPFAM; SSF55785; SSF55785; 1.
DR PROSITE; PS50112; PAS; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Biological rhythms; Cytoplasm; Nucleus; Phosphoprotein;
KW Repeat; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..1248
FT /note="Period circadian protein homolog 2"
FT /id="PRO_0000261153"
FT DOMAIN 175..242
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 315..381
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 389..432
FT /note="PAC"
FT REGION 1..57
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 467..563
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 474..478
FT /note="Important for protein stability"
FT /evidence="ECO:0000250|UniProtKB:Q9Z301"
FT REGION 506..706
FT /note="CSNK1E binding domain"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT REGION 619..638
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 675..708
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 751..829
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 873..1058
FT /note="Interaction with PPARG"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT REGION 950..971
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 984..1035
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1057..1113
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1148..1248
FT /note="CRY binding domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Z301"
FT REGION 1215..1248
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 105..114
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOTIF 302..306
FT /note="LXXLL"
FT MOTIF 456..465
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOTIF 773..789
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOTIF 974..981
FT /note="Nuclear export signal 3"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOTIF 1042..1046
FT /note="LXXLL"
FT COMPBIAS 1..49
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 471..498
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 533..563
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 813..827
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 990..1005
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1014..1035
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1057..1105
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 524
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 527
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 540
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 656
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15055"
FT MOD_RES 690
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 694
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 703
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 755
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 930
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 955
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 962
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
FT MOD_RES 1117
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O54943"
SQ SEQUENCE 1248 AA; 135129 MW; 0FE80D7CA7587A57 CRC64;
MNGYVEFSPS PTKESVEPQP SQAVLQEDVD MSSGSSGHEN CSMGRDSQGS DCDDNGKELR
MLVEPSDTHS SPDAFRLMMT EPQHNPSTSG CSSEQSAKAN AHKELIRTLR ELKVHLPADK
KAKGKASTLA ILKYALRSVK QVKANEEYYQ LLMSSESQPC SMDVPSYTVE QVEGITSEYI
VKNADMFAVA VSLVSGKILY ISNQVASIFH CKKDAFSDAK FVEFLAPHDV SVFHSYTTPY
KLPPWSMCCG VDSFTQECME EKSFFCRVSV GKHHESEIRY QPFRMTPYLV KVQEQQGAES
QLCCLLLAER IHSGYEAPRI PPEKRIFTTT HIPNCLFQDV DERAVPLLGY LPQDLIETPV
LVQLHPSDRP LMLAIHKKIL QAGGQPFDYS PIRFRARNGE YITLDTSWSS FINPWSRKIS
FIIGRHKVRV GPLNEDVFAA SPCPEGKTPH PSIQELTEQI HRLLMQPVPH SGSSGYGSLG
SNGSHEHLMS QTSSSDSNGH EESRWRKSGI SKNGSKTQTR SHFSHESGEQ KEIAVTEMQS
STPAQAKAAP TVERDSSGSS LPKASFPEEL AYKNQPACSY QQISCLDSVI RYLESCNEAA
TLKRKCEFPA NIPSRKATVS PGLHAEEAAP PPSKVSSHAE VRARLSSLTL PDKAESVVSL
TSQCSYSSTI VHVGDKKPQP ELETVEDAVS GPESLDGAPG GLSQEKGPLQ KLGLTKEVLA
AHTQREEQGF LQRFREVSRL GALQAHRQNY RAQASERAAP GLRNASGMDS SWKKTGKNRK
LKSKRVKTRD SSESTGSGGP VSHRPPLVGL NATAWSPSDT SQSSCPSAPF PAPVPAYPLP
VFEAPGITST PAPPEAAHSS FTVPVVPMGA QPDFAVQPLP LAAPLAPVLA FMLPSYPFPP
ANPNLSHAFF PGQPHFPAQP TFASEMTPAS QADFPSQTPL LRQQCTCPVT PPAATVTSGR
ASPPLFQSRG SSPLQLNLLQ LEEAPEGSTG AAGTSGTTGT AAAGLDCTPG TSRDRQPKAP
STCKEPSDTQ NSDALSTSSD LLNLLLAEDL CSATGSALSG SGASATSDSL GSGSLGCDAS
RSGAGSSDTS HTSKYFGSID SSENNHKAKV STDTEESEQF IKYVLQDPIW LLVANTDDSV
MMTYQLPSRD LESVLREGRE RLKLLQRAQP RFTEGQRREL REVHPWVQTG GLPAAIDVAE
CVYCKSERKG DICLPYEEDS PSPGLCDTSE AKEEEGEQLT GPRIEAQT
