Reviewed, UniProtKB/Swiss-Prot O15055 (PER2_HUMAN)

Names and origin

Protein names

Recommended name:
    Period circadian protein homolog 2
Alternative name(s):
    Circadian clock protein PERIOD 2
      Short name=hPER2

Gene names

Name:	PER2
Synonyms:	KIAA0347

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1255 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Component of the circadian clock mechanism which is essential for generating circadian rhythms. Negative element in the circadian transcriptional loop. Influences clock function by interacting with other circadian regulatory proteins and transporting them to the nucleus. Negatively regulates CLOCK|NPAS2-BMAL1|BMAL2-induced transactivation By similarity.
Subunit structure	Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interaction with CSNK1D or CSNK1E promotes nuclear location of PER proteins. Interacts, via its second PAS domain, with TIMELESS in vitro. Interacts with NFIL3 By similarity.
Subcellular location	NucleusBy similarity. CytoplasmBy similarity. Note= Mainly nuclear. Nucleocytoplasmic shuttling is effected by interaction with other circadian core oscillator proteins and/or by phosphorylation. Retention of PER1 in the cytoplasm occurs through PER1-PER2 heterodimer formation or by interaction with CSNK1E and/or phosphorylation which appears to mask the PER nuclear localization signal. Also translocated to the nucleus by CRY1 or CRY2 By similarity.
Tissue specificity	Widely expressed. Found in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low level in lung. Ref.6
Induction	Serum-induced levels in fibroblasts show circadian oscillations. Maximum levels after 1 hour stimulation, minimum levels after 12 hours. Another peak is then observed after 24 hours. Ref.7
Post-translational modification	Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. Ref.2 Ref.8
Involvement in disease	Defects in PER2 are a cause of familial advanced sleep-phase syndrome (FASPS) [MIM:604348]. FASPS is characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. Ref.8
Sequence similarities	Contains 1 PAC (PAS-associated C-terminal) domain. Contains 2 PAS (PER-ARNT-SIM) domains.

Ontologies

Keywords
Biological process	Biological rhythms Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	circadian rhythm Ref.6 Traceable author statement. Source: ProtInc regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: InterPro signal transduction Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	protein binding Inferred from physical interaction. Source: IntAct signal transducer activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CSNK1E	P49674	1	EBI-1054296,EBI-749343

Alternative products

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
     405-1255: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1255	1255	Period circadian protein homolog 2		PRO_0000162630
Regions
	Domain	181 – 248	68	PAS 1
	Domain	321 – 387	67	PAS 2
	Domain	395 – 438	44	PAC
	Region	557 – 771	215	CSNK1E binding domain By similarity
	Region	1155 – 1255	101	CRY binding domain By similarity
	Motif	459 – 471	13	Nuclear export signal By similarity
	Motif	789 – 805	17	Nuclear localization signal By similarity
	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.8
	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	864	1	Phosphothreonine By similarity
	Modified residue	945	1	Phosphoserine By similarity
	Modified residue	977	1	Phosphoserine By similarity
	Modified residue	1124	1	Phosphoserine By similarity
Natural variations
	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: dbSNP rs35572922.		VAR_051575
	Natural variant	662	1	S → G in FASPS; reduced in vitro phosphorylation by CSNK1E. Ref.8		VAR_029080
	Natural variant	729	1	V → I: dbSNP rs4429421.		VAR_051576
	Natural variant	823	1	L → V in a breast cancer sample; somatic mutation. Ref.9		VAR_036041
	Natural variant	903	1	V → I: dbSNP rs35333999.		VAR_051577
	Natural variant	949	1	F → Y: dbSNP rs35998480.		VAR_051578
	Natural variant	1244	1	G → E: dbSNP rs934945.		VAR_024558
Experimental info
	Mutagenesis	662	1	S → D: Restores CSNK1E-dependent phosphorylation of variant G-662 Ref.8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 11, 2001. Version 2. Checksum: 2AEF2C6BD4B6CBB0	FASTA	1,255	136,579
	10 20 30 40 50 60 MNGYAEFPPS PSNPTKEPVE PQPSQVPLQE DVDMSSGSSG HETNENCSTG RDSQGSDCDD 70 80 90 100 110 120 SGKELGMLVE PPDARQSPDT FSLMMAKSEH NPSTSGCSSD QSSKVDTHKE LIKTLKELKV 130 140 150 160 170 180 HLPADKKAKG KASTLATLKY ALRSVKQVKA NEEYYQLLMS SEGHPCGADV PSYTVEEMES 190 200 210 220 230 240 VTSEHIVKNA DMFAVAVSLV SGKILYISDQ VASIFHCKRD AFSDAKFVEF LAPHDVGVFH 250 260 270 280 290 300 SFTSPYKLPL WSMCSGADSF TQECMEEKSF FCRVSVRKSH ENEIRYHPFR MTPYLVKVRD 310 320 330 340 350 360 QQGAESQLCC LLLAERVHSG YEAPRIPPEK RIFTTTHTPN CLFQDVDERA VPLLGYLPQD 370 380 390 400 410 420 LIETPVLVQL HPSDRPLMLA IHKKILQSGG QPFDYSPIRF RARNGEYITL DTSWSSFINP 430 440 450 460 470 480 WSRKISFIIG RHKVRVGPLN EDVFAAHPCT EEKALHPSIQ ELTEQIHRLL LQPVPHSGSS 490 500 510 520 530 540 GYGSLGSNGS HEHLMSQTSS SDSNGHEDSR RRRAEICKNG NKTKNRSHYS HESGEQKKKS 550 560 570 580 590 600 VTEMQTNPPA EKKAVPAMEK DSLGVSFPEE LACKNQPTCS YQQISCLDSV IRYLESCNEA 610 620 630 640 650 660 ATLKRKCEFP ANVPALRSSD KRKATVSPGP HAGEAEPPSR VNSRTGVGTH LTSLALPGKA 670 680 690 700 710 720 ESVASLTSQC SYSSTIVHVG DKKPQPELEM VEDAASGPES LDCLAGPALA CGLSQEKEPF 730 740 750 760 770 780 KKLGLTKEVL AAHTQKEEQS FLQKFKEIRK LSIFQSHCHY YLQERSKGQP SERTAPGLRN 790 800 810 820 830 840 TSGIDSPWKK TGKNRKLKSK RVKPRDSSES TGSGGPVSAR PPLVGLNATA WSPSDTSQSS 850 860 870 880 890 900 CPAVPFPAPV PAAYSLPVFP APGTVAAPPA PPHASFTVPA VPVDLQHQFA VQPPPFPAPL 910 920 930 940 950 960 APVMAFMLPS YSFPSGTPNL PQAFFPSQPQ FPSHPTLTSE MASASQPEFP SRTSIPRQPC 970 980 990 1000 1010 1020 ACPATRATPP SAMGRASPPL FQSRSSSPLQ LNLLQLEEAP EGGTGAMGTT GATETAAVGA 1030 1040 1050 1060 1070 1080 DCKPGTSRDQ QPKAPLTRDE PSDTQNSDAL STSSGLLNLL LNEDLCSASG SAASESLGSG 1090 1100 1110 1120 1130 1140 SLGCDASPSG AGSSDTSHTS KYFGSIDSSE NNHKAKMNTG MEESEHFIKC VLQDPIWLLM 1150 1160 1170 1180 1190 1200 ADADSSVMMT YQLPSRNLEA VLKEDREKLK LLQKLQPRFT ESQKQELREV HQWMQTGGLP 1210 1220 1230 1240 1250 AAIDVAECVY CENKEKGNIC IPYEEDIPSL GLSEVSDTKE DENGSPLNHR IEEQT
	Isoform 2 (PER2S). Checksum: B6DED6DD2AC3F971		404	45,175
	10 20 30 40 50 60 MNGYAEFPPS PSNPTKEPVE PQPSQVPLQE DVDMSSGSSG HETNENCSTG RDSQGSDCDD 70 80 90 100 110 120 SGKELGMLVE PPDARQSPDT FSLMMAKSEH NPSTSGCSSD QSSKVDTHKE LIKTLKELKV 130 140 150 160 170 180 HLPADKKAKG KASTLATLKY ALRSVKQVKA NEEYYQLLMS SEGHPCGADV PSYTVEEMES 190 200 210 220 230 240 VTSEHIVKNA DMFAVAVSLV SGKILYISDQ VASIFHCKRD AFSDAKFVEF LAPHDVGVFH 250 260 270 280 290 300 SFTSPYKLPL WSMCSGADSF TQECMEEKSF FCRVSVRKSH ENEIRYHPFR MTPYLVKVRD 310 320 330 340 350 360 QQGAESQLCC LLLAERVHSG YEAPRIPPEK RIFTTTHTPN CLFQDVDESP AVRRAAFRLF 370 380 390 400 SHSVSRPERR VHHVGHQLVQ LHQPMEQENL LHHWEAQSQG GPFE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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). Tissue: Brain.
[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: 11165242] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PHOSPHORYLATION, INTERACTION WTIN CSNK1D. Tissue: Brain.
[3]	"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: 9205841] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[4]	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.
[5]	"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. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 9427249] [Abstract] Cited for: TISSUE SPECIFICITY.
[7]	"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: 14750904] [Abstract] Cited for: INDUCTION.
[8]	"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: 11232563] [Abstract] Cited for: VARIANT FASPS GLY-662, INTERACTION WITH CSNK1E, PHOSPHORYLATION AT SER-662, MUTAGENESIS OF SER-662.
[9]	"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. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-823.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AB012614 mRNA. Translation: BAA83709.1. AB002345 mRNA. Translation: BAA20804.2. Different initiation. AC012485 Genomic DNA. Translation: AAX88976.1.
RefSeq	NP_073728.1.
UniGene	Hs.58756
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	O15055. 2 interactions.
PTM databases
PhosphoSite	O15055.
Proteomic databases
PRIDE	O15055.
Genome annotation databases
Ensembl	ENSG00000132326. Homo sapiens. [Contig view]
GeneID	8864.
KEGG	hsa:8864.
Organism-specific databases
GeneCards	GC02M238817.
H-InvDB	HIX0022994.
HGNC	HGNC:8846. PER2.
MIM	603426. gene. 604348. phenotype.
PharmGKB	PA38691.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O15055.
HOVERGEN	O15055.
Gene expression databases
ArrayExpress	O15055.
CleanEx	HS_PER2.
GermOnline	ENSG00000132326. Homo sapiens.
Family and domain databases
InterPro	IPR001610. PAC. IPR000014. PAS. IPR000700. PAS-assoc_C. IPR013655. PAS_3. [Graphical view]
Pfam	PF08447. PAS_3. 1 hit. [Graphical view]
SMART	SM00086. PAC. 1 hit. SM00091. PAS. 2 hits. [Graphical view]
PROSITE	PS50113. PAC. False negative. PS50112. PAS. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	33285.
SOURCE	Search...

Entry information

Entry name

PER2_HUMAN

Accession

Primary (citable) accession number: O15055
Secondary accession number(s): Q4ZG49, Q9UQ45

Entry history

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Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	July 11, 2001