O15055 (PER2_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 137. History...
Names and origin
|Protein names||Recommended name:|
Period circadian protein homolog 2
Circadian clock protein PERIOD 2
|Organism||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||1255 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 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.
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. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Ref.2 Ref.12
Isoform 1: Nucleus. Cytoplasm By similarity. Cytoplasm › perinuclear 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. Ref.12 Ref.13
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). Ref.9 Ref.13
Oscillates diurnally. 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. Ref.10
Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibit by CRY1 By similarity.
|Involvement in disease|
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.
Contains 1 PAC (PAS-associated C-terminal) domain.
Contains 2 PAS (PER-ARNT-SIM) domains.
The sequence BAA20804.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O15055-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: O15055-2) |
Also known as: PER2S;
The sequence of this isoform differs from the canonical sequence as follows:
349-404: RAVPLLGYLP...YSPIRFRARN → SPAVRRAAFR...EAQSQGGPFE
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 1255||1255||Period circadian protein homolog 2||PRO_0000162630|
|Domain||181 – 248||68||PAS 1|
|Domain||321 – 387||67||PAS 2|
|Domain||395 – 438||44||PAC|
|Region||480 – 484||5||Important for protein stability By similarity|
|Region||557 – 771||215||CSNK1E binding domain By similarity|
|Region||888 – 1071||184||Interaction with PPARG By similarity|
|Region||1155 – 1255||101||CRY binding domain By similarity|
|Motif||111 – 120||10||Nuclear export signal 1 By similarity|
|Motif||308 – 312||5||LXXLL|
|Motif||462 – 471||10||Nuclear export signal 3 By similarity|
|Motif||789 – 805||17||Nuclear localization signal By similarity|
|Motif||989 – 996||8||Nuclear export signal 2 By similarity|
|Motif||1057 – 1061||5||LXXLL|
|Compositional bias||510 – 513||4||Poly-Arg|
|Compositional bias||842 – 979||138||Pro-rich|
Amino acid modifications
|Modified residue||527||1||Phosphoserine By similarity|
|Modified residue||530||1||Phosphoserine By similarity|
|Modified residue||533||1||Phosphoserine By similarity|
|Modified residue||540||1||Phosphoserine By similarity|
|Modified residue||662||1||Phosphoserine Ref.16|
|Modified residue||696||1||Phosphoserine By similarity|
|Modified residue||700||1||Phosphoserine By similarity|
|Modified residue||714||1||Phosphoserine By similarity|
|Modified residue||766||1||Phosphoserine By similarity|
|Modified residue||771||1||Phosphoserine By similarity|
|Modified residue||945||1||Phosphoserine By similarity|
|Modified residue||977||1||Phosphoserine By similarity|
|Modified residue||1124||1||Phosphoserine By similarity|
|Alternative sequence||349 – 404||56||RAVPL…FRARN → SPAVRRAAFRLFSHSVSRPE RRVHHVGHQLVQLHQPMEQE NLLHHWEAQSQGGPFE in isoform 2.||VSP_021653|
|Alternative sequence||405 – 1255||851||Missing in isoform 2.||VSP_021654|
|Natural variant||5||1||A → S.|
Corresponds to variant rs35572922 [ dbSNP | Ensembl ].
|Natural variant||662||1||S → G in FASPS1; reduced in vitro phosphorylation by CSNK1E. Ref.16||VAR_029080|
|Natural variant||729||1||V → I.|
Corresponds to variant rs4429421 [ dbSNP | Ensembl ].
|Natural variant||823||1||L → V in a breast cancer sample; somatic mutation. Ref.17||VAR_036041|
|Natural variant||903||1||V → I.|
Corresponds to variant rs35333999 [ dbSNP | Ensembl ].
|Natural variant||949||1||F → Y.|
Corresponds to variant rs35998480 [ dbSNP | Ensembl ].
|Natural variant||1244||1||G → E.|
Corresponds to variant rs934945 [ dbSNP | Ensembl ].
|Mutagenesis||662||1||S → D: Restores CSNK1E-dependent phosphorylation of variant G-662. Ref.16|
|||"cDNA cloning and characterization of Per2S, an alternatively spliced human Per2 variant."|
Ikeda M., Takehara N., Ebisawa T., Yamauchi T., Nomura M.
Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
|||"Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2."|
Camacho F., Cilio M., Guo Y., Virshup D.M., Patel K., Khorkova O., Styren S., Morse B., Yao Z., Keesler G.A.
FEBS Lett. 489:159-165(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PHOSPHORYLATION, INTERACTION WITH CSNK1D.
|||NHLBI resequencing and genotyping service (RS&G)|
Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||"Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."|
Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 4:141-150(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
|||Nagase T., Ishikawa K., Seki N., Nakajima D., Ohira M., Miyajima N., Kotani H., Nomura N., Ohara O.|
Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION TO C-TERMINUS.
|||"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."|
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. Venter J.C.|
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference."|
Carpen J.D., Archer S.N., Skene D.J., Smits M., von Schantz M.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-65.
|||"Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei."|
Shearman L.P., Zylka M.J., Weaver D.R., Kolakowski L.F. Jr., Reppert S.M.
Neuron 19:1261-1269(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
|||"Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts."|
Miyazaki K., Nagase T., Mesaki M., Narukawa J., Ohara O., Ishida N.
Biochem. J. 380:95-103(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
|||"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."|
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"PML regulates PER2 nuclear localization and circadian function."|
Miki T., Xu Z., Chen-Goodspeed M., Liu M., Van Oort-Jansen A., Rea M.A., Zhao Z., Lee C.C., Chang K.S.
EMBO J. 31:1427-1439(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH PML.
|||"Nucleolar localization and circadian regulation of Per2S, a novel splicing variant of the Period 2 gene."|
Avitabile D., Genovese L., Ponti D., Ranieri D., Raffa S., Calogero A., Torrisi M.R.
Cell. Mol. Life Sci. 0:0-0(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORM 2), SUBCELLULAR LOCATION (ISOFORM 2), TISSUE SPECIFICITY (ISOFORM 2).
|||"Metabolism and the circadian clock converge."|
Eckel-Mahan K., Sassone-Corsi P.
Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|||"Molecular architecture of the mammalian circadian clock."|
Partch C.L., Green C.B., Takahashi J.S.
Trends Cell Biol. 24:90-99(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|||"An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome."|
Toh K.L., Jones C.R., He Y., Eide E.J., Hinz W.A., Virshup D.M., Ptacek L.J., Fu Y.-H.
Science 291:1040-1043(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT FASPS1 GLY-662, PHOSPHORYLATION AT SER-662, MUTAGENESIS OF SER-662.
|||"The consensus coding sequences of human breast and colorectal cancers."|
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. Velculescu V.E.
Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-823.
|+||Additional computationally mapped references.|
|AB012614 mRNA. Translation: BAA83709.1.|
EF015905 Genomic DNA. Translation: ABM64216.1.
AB002345 mRNA. Translation: BAA20804.2. Different initiation.
AC012485 Genomic DNA. Translation: AAX88976.1.
CH471063 Genomic DNA. Translation: EAW71155.1.
AY647991 Genomic DNA. Translation: AAT68170.1.
|RefSeq||NP_073728.1. NM_022817.2. [O15055-1]|
XP_005246168.1. XM_005246111.2. [O15055-1]
XP_006712887.1. XM_006712824.1. [O15055-1]
3D structure databases
|SMR||O15055. Positions 115-475. |
Protein-protein interaction databases
|BioGrid||114387. 10 interactions.|
|IntAct||O15055. 2 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000254657; ENSP00000254657; ENSG00000132326. [O15055-1]|
ENST00000254658; ENSP00000254658; ENSG00000132326. [O15055-2]
ENST00000355768; ENSP00000348013; ENSG00000132326. [O15055-2]
|UCSC||uc002vyc.3. human. [O15055-1]|
uc010fyx.1. human. [O15055-2]
|HGNC||HGNC:8846. PER2. |
|MIM||603426. gene. |
|Orphanet||164736. Familial advanced sleep-phase syndrome. |
Enzyme and pathway databases
|Reactome||REACT_24941. Circadian Clock. |
Gene expression databases
Family and domain databases
|InterPro||IPR001610. PAC. |
|Pfam||PF12114. Period_C. 1 hit. |
|SMART||SM00086. PAC. 1 hit. |
SM00091. PAS. 2 hits.
|SUPFAM||SSF55785. SSF55785. 1 hit. |
|PROSITE||PS50112. PAS. 1 hit. |
|Accession||Primary (citable) accession number: O15055|
Secondary accession number(s): A2I2P7 Q9UQ45
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
|Disclaimer||Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.|
Index of protein domains and families
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
|Human polymorphisms and disease mutations|
Index of human polymorphisms and disease mutations
|Human entries with polymorphisms or disease mutations|
List of human entries with polymorphisms or disease mutations
|Human chromosome 2|
Human chromosome 2: entries, gene names and cross-references to MIM