dbPTM

PER2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	PER2_HUMAN
UniProt AC	O15055
Protein Name	Period circadian protein homolog 2
Gene Name	PER2
Organism	Homo sapiens (Human).
Sequence Length	1255
Subcellular Localization	Isoform 1: Nucleus. Cytoplasm . Cytoplasm, perinuclear region. Nucleocytoplasmic shuttling is effected by interaction with other circadian core oscillator proteins and/or by phosphorylation. Translocate to the nucleus after phosphorylation by CSNK1D
Protein Description	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 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 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1..
Protein Sequence	MNGYAEFPPSPSNPTKEPVEPQPSQVPLQEDVDMSSGSSGHETNENCSTGRDSQGSDCDDSGKELGMLVEPPDARQSPDTFSLMMAKSEHNPSTSGCSSDQSSKVDTHKELIKTLKELKVHLPADKKAKGKASTLATLKYALRSVKQVKANEEYYQLLMSSEGHPCGADVPSYTVEEMESVTSEHIVKNADMFAVAVSLVSGKILYISDQVASIFHCKRDAFSDAKFVEFLAPHDVGVFHSFTSPYKLPLWSMCSGADSFTQECMEEKSFFCRVSVRKSHENEIRYHPFRMTPYLVKVRDQQGAESQLCCLLLAERVHSGYEAPRIPPEKRIFTTTHTPNCLFQDVDERAVPLLGYLPQDLIETPVLVQLHPSDRPLMLAIHKKILQSGGQPFDYSPIRFRARNGEYITLDTSWSSFINPWSRKISFIIGRHKVRVGPLNEDVFAAHPCTEEKALHPSIQELTEQIHRLLLQPVPHSGSSGYGSLGSNGSHEHLMSQTSSSDSNGHEDSRRRRAEICKNGNKTKNRSHYSHESGEQKKKSVTEMQTNPPAEKKAVPAMEKDSLGVSFPEELACKNQPTCSYQQISCLDSVIRYLESCNEAATLKRKCEFPANVPALRSSDKRKATVSPGPHAGEAEPPSRVNSRTGVGTHLTSLALPGKAESVASLTSQCSYSSTIVHVGDKKPQPELEMVEDAASGPESLDCLAGPALACGLSQEKEPFKKLGLTKEVLAAHTQKEEQSFLQKFKEIRKLSIFQSHCHYYLQERSKGQPSERTAPGLRNTSGIDSPWKKTGKNRKLKSKRVKPRDSSESTGSGGPVSARPPLVGLNATAWSPSDTSQSSCPAVPFPAPVPAAYSLPVFPAPGTVAAPPAPPHASFTVPAVPVDLQHQFAVQPPPFPAPLAPVMAFMLPSYSFPSGTPNLPQAFFPSQPQFPSHPTLTSEMASASQPEFPSRTSIPRQPCACPATRATPPSAMGRASPPLFQSRSSSPLQLNLLQLEEAPEGGTGAMGTTGATETAAVGADCKPGTSRDQQPKAPLTRDEPSDTQNSDALSTSSGLLNLLLNEDLCSASGSAASESLGSGSLGCDASPSGAGSSDTSHTSKYFGSIDSSENNHKAKMNTGMEESEHFIKCVLQDPIWLLMADADSSVMMTYQLPSRNLEAVLKEDREKLKLLQKLQPRFTESQKQELREVHQWMQTGGLPAAIDVAECVYCENKEKGNICIPYEEDIPSLGLSEVSDTKEDENGSPLNHRIEEQT

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
24	Phosphorylation	EPVEPQPSQVPLQED CCCCCCCCCCCCCCC	38.26	22468782
35	Phosphorylation	LQEDVDMSSGSSGHE CCCCCCCCCCCCCCC	27.38	22468782
38	Phosphorylation	DVDMSSGSSGHETNE CCCCCCCCCCCCCCC	34.79	22468782
43	Phosphorylation	SGSSGHETNENCSTG CCCCCCCCCCCCCCC	42.00	22468782
56	Phosphorylation	TGRDSQGSDCDDSGK CCCCCCCCCCCCCCC	27.68	28985074
77	Phosphorylation	EPPDARQSPDTFSLM CCCCHHCCCCCCHHH	21.13	26074081
80	Phosphorylation	DARQSPDTFSLMMAK CHHCCCCCCHHHEEE	20.64	26074081
82	Phosphorylation	RQSPDTFSLMMAKSE HCCCCCCHHHEEECC	19.90	26074081
88	Phosphorylation	FSLMMAKSEHNPSTS CHHHEEECCCCCCCC	34.25	26074081
98	Phosphorylation	NPSTSGCSSDQSSKV CCCCCCCCCCCCCCC	40.24	28985074
113	Ubiquitination	DTHKELIKTLKELKV HHHHHHHHHHHHHHC	61.50	29967540
259	Phosphorylation	SMCSGADSFTQECME HHCCCCCHHHHHHHH	29.65	28348404
286	Phosphorylation	SHENEIRYHPFRMTP CCCCCCEECCCCCCC	21.36	26074081
292	Phosphorylation	RYHPFRMTPYLVKVR EECCCCCCCEEEEEE	12.43	26074081
294	Phosphorylation	HPFRMTPYLVKVRDQ CCCCCCCEEEEEECC	18.24	26074081
383	Ubiquitination	PLMLAIHKKILQSGG CEEHHHHHHHHHCCC	35.08	22817900
384 (in isoform 1)	Ubiquitination	-	34.19	21890473
384	Ubiquitination	LMLAIHKKILQSGGQ EEHHHHHHHHHCCCC	34.19	22817900
384	Ubiquitination	LMLAIHKKILQSGGQ EEHHHHHHHHHCCCC	34.19	21890473
388	Phosphorylation	IHKKILQSGGQPFDY HHHHHHHCCCCCCCC	41.25	22210691
395	Phosphorylation	SGGQPFDYSPIRFRA CCCCCCCCCCEEEEE	19.41	22210691
396	Phosphorylation	GGQPFDYSPIRFRAR CCCCCCCCCEEEEEE	18.72	22210691
453	Ubiquitination	AHPCTEEKALHPSIQ CCCCCHHHHHCHHHH	50.44	29967540
480	Phosphorylation	PVPHSGSSGYGSLGS CCCCCCCCCCCCCCC	39.29	-
527	Phosphorylation	GNKTKNRSHYSHESG CCCCCCCCCCCCCCC	35.85	-
530	Phosphorylation	TKNRSHYSHESGEQK CCCCCCCCCCCCCCC	18.50	-
533	Phosphorylation	RSHYSHESGEQKKKS CCCCCCCCCCCCCCC	42.05	-
539	Acetylation	ESGEQKKKSVTEMQT CCCCCCCCCCCCCCC	58.14	7964137
540	Phosphorylation	SGEQKKKSVTEMQTN CCCCCCCCCCCCCCC	43.05	25159151
542	Phosphorylation	EQKKKSVTEMQTNPP CCCCCCCCCCCCCCH	32.60	28348404
553	Acetylation	TNPPAEKKAVPAMEK CCCHHHHCCCCCCCC	46.23	7964147
566	O-linked_Glycosylation	EKDSLGVSFPEELAC CCCCCCCCCCHHHHC	33.03	30379171
580	O-linked_Glycosylation	CKNQPTCSYQQISCL CCCCCCCCHHHHHHH	28.58	30379171
618	Phosphorylation	ANVPALRSSDKRKAT CCCCCCCCCCCCCCC	43.68	20068231
619	Phosphorylation	NVPALRSSDKRKATV CCCCCCCCCCCCCCC	40.49	20068231
625	Phosphorylation	SSDKRKATVSPGPHA CCCCCCCCCCCCCCC	25.26	30266825
627	Phosphorylation	DKRKATVSPGPHAGE CCCCCCCCCCCCCCC	21.56	25849741
639	Phosphorylation	AGEAEPPSRVNSRTG CCCCCCCCCCCCCCC	60.62	27251275
643	Phosphorylation	EPPSRVNSRTGVGTH CCCCCCCCCCCCCCC	28.50	27251275
645	Phosphorylation	PSRVNSRTGVGTHLT CCCCCCCCCCCCCHH	35.72	21712546
649	Phosphorylation	NSRTGVGTHLTSLAL CCCCCCCCCHHEECC	16.00	21712546
652	Phosphorylation	TGVGTHLTSLALPGK CCCCCCHHEECCCCC	17.68	21712546
653	O-linked_Glycosylation	GVGTHLTSLALPGKA CCCCCHHEECCCCCH	20.29	30379171
653	Phosphorylation	GVGTHLTSLALPGKA CCCCCHHEECCCCCH	20.29	-
662	Phosphorylation	ALPGKAESVASLTSQ CCCCCHHHHHHHHHC	28.04	11475410
662	O-linked_Glycosylation	ALPGKAESVASLTSQ CCCCCHHHHHHHHHC	28.04	11475410
665	Phosphorylation	GKAESVASLTSQCSY CCHHHHHHHHHCCCC	29.99	21324900
668	O-linked_Glycosylation	ESVASLTSQCSYSST HHHHHHHHCCCCCEE	34.19	17218255
668	Phosphorylation	ESVASLTSQCSYSST HHHHHHHHCCCCCEE	34.19	21324900
671	O-linked_Glycosylation	ASLTSQCSYSSTIVH HHHHHCCCCCEEEEE	22.03	17218255
671	Phosphorylation	ASLTSQCSYSSTIVH HHHHHCCCCCEEEEE	22.03	17218255
674	Phosphorylation	TSQCSYSSTIVHVGD HHCCCCCEEEEECCC	17.58	17218255
696	Phosphorylation	EMVEDAASGPESLDC EECCHHHHCCCHHHH	57.51	23898821
700	Phosphorylation	DAASGPESLDCLAGP HHHHCCCHHHHHHHH	32.42	28348404
714	Phosphorylation	PALACGLSQEKEPFK HHHHCCCCCCCCHHH	22.90	-
734	O-linked_Glycosylation	KEVLAAHTQKEEQSF HHHHHHHCHHHHHHH	36.29	30379171
744	Ubiquitination	EEQSFLQKFKEIRKL HHHHHHHHHHHHHHH	61.63	29967540
766	Phosphorylation	HYYLQERSKGQPSER HHHHHHHHCCCCCCC	40.15	27251275
771	Phosphorylation	ERSKGQPSERTAPGL HHHCCCCCCCCCCCC	31.64	23898821
774	Phosphorylation	KGQPSERTAPGLRNT CCCCCCCCCCCCCCC	32.90	23898821
781	Phosphorylation	TAPGLRNTSGIDSPW CCCCCCCCCCCCCCH	23.15	27251275
782	Phosphorylation	APGLRNTSGIDSPWK CCCCCCCCCCCCCHH	36.98	27251275
786	Phosphorylation	RNTSGIDSPWKKTGK CCCCCCCCCHHHCCC	30.64	30624053
810	Phosphorylation	KPRDSSESTGSGGPV CCCCCCCCCCCCCCC	39.76	-
945	Phosphorylation	TSEMASASQPEFPSR CHHHHHCCCCCCCCC	43.71	-
965	O-linked_Glycosylation	QPCACPATRATPPSA CCCCCCCCCCCCCHH	13.13	30379171
968	Phosphorylation	ACPATRATPPSAMGR CCCCCCCCCCHHHCC	32.23	24719451
971	Phosphorylation	ATRATPPSAMGRASP CCCCCCCHHHCCCCC	31.90	28985074
977	Phosphorylation	PSAMGRASPPLFQSR CHHHCCCCCCCCCCC	26.20	23401153
983	Phosphorylation	ASPPLFQSRSSSPLQ CCCCCCCCCCCCCCE	27.13	28985074
983	O-linked_Glycosylation	ASPPLFQSRSSSPLQ CCCCCCCCCCCCCCE	27.13	30379171
985	Phosphorylation	PPLFQSRSSSPLQLN CCCCCCCCCCCCEEE	40.18	28857561
986	Phosphorylation	PLFQSRSSSPLQLNL CCCCCCCCCCCEEEE	34.56	28348404
987	Phosphorylation	LFQSRSSSPLQLNLL CCCCCCCCCCEEEEE	30.76	28348404
1010	Phosphorylation	GTGAMGTTGATETAA CCCCCCCCCCCCCCC	21.06	28857561
1013	Phosphorylation	AMGTTGATETAAVGA CCCCCCCCCCCCCCC	34.90	28857561
1015	Phosphorylation	GTTGATETAAVGADC CCCCCCCCCCCCCCC	18.63	28857561
1026	Phosphorylation	GADCKPGTSRDQQPK CCCCCCCCCCCCCCC	29.17	28857561
1105	Phosphorylation	HTSKYFGSIDSSENN CCHHCCCCCCCCCCC	17.21	25849741
1108	Phosphorylation	KYFGSIDSSENNHKA HCCCCCCCCCCCHHH	37.57	25849741
1109	Phosphorylation	YFGSIDSSENNHKAK CCCCCCCCCCCHHHH	40.36	25849741
1124	Phosphorylation	MNTGMEESEHFIKCV CCCCCCHHHHHHHHH	24.06	-
1180	O-linked_Glycosylation	QKLQPRFTESQKQEL HHHHHCCCHHHHHHH	35.69	30379171
1184	Ubiquitination	PRFTESQKQELREVH HCCCHHHHHHHHHHH	55.83	29967540
1233	Phosphorylation	DIPSLGLSEVSDTKE CCCCCCCCCCCCCCC	33.87	27251275
1236	Phosphorylation	SLGLSEVSDTKEDEN CCCCCCCCCCCCCCC	35.20	27251275
1238	Phosphorylation	GLSEVSDTKEDENGS CCCCCCCCCCCCCCC	28.91	27251275
1245	Phosphorylation	TKEDENGSPLNHRIE CCCCCCCCCCCHHCC	37.48	25849741

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
53	S	Phosphorylation	Kinase	CK2-FAMILY	-	GPS
480	S	Phosphorylation	Kinase	CK1E	P49674	PSP
662	S	Phosphorylation	Kinase	CSNK1D	P48730	GPS
662	S	Phosphorylation	Kinase	CSNK1E	P49674	GPS
665	S	Phosphorylation	Kinase	CSNK1D	P48730	GPS
665	S	Phosphorylation	Kinase	CSNK1E	P49674	GPS
668	S	Phosphorylation	Kinase	CSNK1D	P48730	GPS
668	S	Phosphorylation	Kinase	CSNK1E	P49674	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	FBXW11	Q9UKB1	PMID:24658274
-	K	Ubiquitination	E3 ubiquitin ligase	BTRC	Q9Y297	PMID:15767683
-	K	Ubiquitination	E3 ubiquitin ligase	MDM2	Q00987	PMID:30425162

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
Oops, there are no descriptions of PTM sites of PER2_HUMAN !!

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of PER2_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CRY1_HUMAN	CRY1	physical	10531061
CRY1_HUMAN	CRY1	physical	11533252
CRY2_HUMAN	CRY2	physical	10531061
FBW1A_HUMAN	BTRC	physical	17463251
P53_HUMAN	TP53	physical	25103245
TCTP_HUMAN	TPT1	physical	25103245
CRY1_HUMAN	CRY1	physical	25103245
MDM2_HUMAN	MDM2	physical	25103245
RORG_HUMAN	RORC	physical	23555304
P53_HUMAN	TP53	physical	27834218
CRY1_HUMAN	CRY1	physical	27834218
PP1A_RABIT	PPP1CA	physical	16813562

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
604348	Advanced sleep phase syndrome, familial, 1 (FASPS1)
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of PER2_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"An hPer2 phosphorylation site mutation in familial advanced sleepphase 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). Cited for: VARIANT FASPS GLY-662, INTERACTION WITH CSNK1E, PHOSPHORYLATION ATSER-662, AND MUTAGENESIS OF SER-662.	11232563 [Abstract]