PER2_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: PER2_RAT
• UniProt AC: Q9Z301
• Protein Name: Period circadian protein homolog 2
• Gene Name: Per2 {ECO:0000312|RGD:61945}
• Organism: Rattus norvegicus (Rat).
• Sequence Length: 1257
• Subcellular Localization: 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 or CSNK1E.
• 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 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: MNGYVDFSPSPTSPTQEPGEPQPTQAVLQEDVDMSSGSSGNENCSTGRDSQGSDCDDSGKELRMLVESSNTHPSPDDTFRLMMTEAEHNPSTSGCSSEQSAKADAHKELIRTLRELKVHLPADKKAKGKASTLATLKYALRSVKQVKANEEYYQLLMSSESQPCSVDVPSYTMEQVEGITSEYIVKNSDMFAVAVSLVSGKILYISNQVAPIFHCKKDAFSDAKFVEFLAPHDVSVFHSYTTPYKLPPWSVSSGLDSFTQECMEEKSFFCRVSVGKHHENEIRYQPFRMTPYLVKVQEQKGAASQLCCLLLAERVHSGYEAPRIPPEKRIFTTTHTPNCLFQDVDERAVPLLGYLPQDLIETPVLVQLHPSDRPLMLAIHKKILQASGQPFDYSPIRFRTRNGEYITLDTSWSSFINPWSRKISFIIGRHKVRVGPLNEDVFAASPCPEEKTPHPSVQELTEQIHRLLMQPVPHSGSSGYGSLGSNGSHEHLMSQTSSSDSNGQEESHWRRSGIFKTSGKSQSKSHFSPESGGQKEASVAEMQSSPPAQVRSVTTMERDSSGASLPKASFPEELTYKSQPPCSYQQISCLDSVIRYLESCNEAATLKRKCEFPANIPSRKATVSPGLHSGEAARSSKVTSHTEVSAHLSSLALPGKAESVVSLTSQCSYSSTIVHVGDKKPQPELETVEDVASGPESQDDAAGGLSQEKGSLQKLGLTKEVLAAHTQREEQGFLQRFREVSRLGALQAHCQNYLQERSRAPASDRGLRNASGIESSWKKTGKNRKLKSKRVKTRDSSESTGSGGPVSHRPPLVGLNATAWSPSDTSQSSCPSAPFPAPVPAYPLPVFPAPGIVSTPGTVVAPPAAAHTGFTMPVVPMGTQPEFAVQPLPFAAPLAPVMAFMLPSYPFPPATPNLPQAFFPSQPHFPAHPTLASEITPASQAEFPSRTSMLRQPCACPVTPPAGTVALGRASPPLFQSRGSSPLQLNLLQLEEAPESSTGAAGTLGTTGTAASGLDCTSGASRDRQPKAPPTCSEPSDTQNSDAISTSSDLLNLLLGEDLCSATGSALSRSGASATSDSLGSSSLGCDTSRSGAGSSDTSHTSKYFGSIDSSENNHKAKMITDTEESEQFIKYVLQDPIWLLMANTDDNIMMTYQLPSRDLQAVLKEDQEKLKLLQRSQPHFTEGQRRELREVHPWVHTGGLPTAIDVTGCVYCESEEKGNLCLPYEEDSPSLGLCDTSEAKEEESGQLANPRKEAQT

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
68	Phosphorylation	ELRMLVESSNTHPSP EEEHHHHCCCCCCCC	22.78	25575281
69	Phosphorylation	LRMLVESSNTHPSPD EEHHHHCCCCCCCCC	32.04	25575281
71	Phosphorylation	MLVESSNTHPSPDDT HHHHCCCCCCCCCHH	36.79	25575281
74	Phosphorylation	ESSNTHPSPDDTFRL HCCCCCCCCCHHHHH	33.10	25575281
78	Phosphorylation	THPSPDDTFRLMMTE CCCCCCHHHHHHEEE	20.31	25575281
221	Phosphorylation	HCKKDAFSDAKFVEF EECCCCCCCCCHHHH	38.08	26022182
525	Phosphorylation	SGKSQSKSHFSPESG CCCCCCCCCCCCCCC	34.70	30181290
528	Phosphorylation	SQSKSHFSPESGGQK CCCCCCCCCCCCCCC	23.49	30181290
531	Phosphorylation	KSHFSPESGGQKEAS CCCCCCCCCCCCCCH	52.16	30181290
538	Phosphorylation	SGGQKEASVAEMQSS CCCCCCCHHHHHHCC	23.97	-
544	Phosphorylation	ASVAEMQSSPPAQVR CHHHHHHCCCCCEEE	43.43	30181290
545	Phosphorylation	SVAEMQSSPPAQVRS HHHHHHCCCCCEEEE	20.29	30181290
554	Phosphorylation	PAQVRSVTTMERDSS CCEEEEEEEEEECCC	22.98	-
622	Phosphorylation	NIPSRKATVSPGLHS CCCCCCEEECCCCCC	25.26	23984901
624	Phosphorylation	PSRKATVSPGLHSGE CCCCEEECCCCCCCH	14.64	29779826
629	Phosphorylation	TVSPGLHSGEAARSS EECCCCCCCHHHHCC	43.29	23984901
659	Phosphorylation	ALPGKAESVVSLTSQ CCCCCCHHEEECCCC	32.45	-
687	Phosphorylation	KPQPELETVEDVASG CCCCCCEEHHHHHCC	41.65	25575281
693	Phosphorylation	ETVEDVASGPESQDD EEHHHHHCCCCCCCC	55.52	22673903
697	Phosphorylation	DVASGPESQDDAAGG HHHCCCCCCCCCCCC	41.88	22673903
706	Phosphorylation	DDAAGGLSQEKGSLQ CCCCCCCCCCCCHHH	39.30	25575281
758	Phosphorylation	QNYLQERSRAPASDR HHHHHHHHCCCCHHH	31.85	-
763	Phosphorylation	ERSRAPASDRGLRNA HHHCCCCHHHCCCCC	27.12	-
858	Phosphorylation	GIVSTPGTVVAPPAA CCCCCCCEEECCCCC	17.01	-
939	Phosphorylation	ASEITPASQAEFPSR HHCCCHHHHCCCCCC	31.00	-
964	Phosphorylation	PVTPPAGTVALGRAS CCCCCCCCEECCCCC	12.52	-
971	Phosphorylation	TVALGRASPPLFQSR CEECCCCCCCCHHCC	26.20	28432305
1089	Phosphorylation	SSLGCDTSRSGAGSS CCCCCCCCCCCCCCC	15.93	26022182
1104	Phosphorylation	DTSHTSKYFGSIDSS CCCCCHHCCCCCCCC	16.97	22673903
1107	Phosphorylation	HTSKYFGSIDSSENN CCHHCCCCCCCCCCC	17.21	22673903
1110	Phosphorylation	KYFGSIDSSENNHKA HCCCCCCCCCCCCCC	37.57	22673903
1111	Phosphorylation	YFGSIDSSENNHKAK CCCCCCCCCCCCCCE	40.36	22673903
1126	Phosphorylation	MITDTEESEQFIKYV ECCCCHHHHHHHHHH	30.39	-

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

Oops, there are no upstream regulatory protein records of PER2_RAT !!

Functions of PTM Sites

Oops, there are no descriptions of PTM sites of PER2_RAT !!

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of PER2_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
FBW1A_MOUSE	Btrc	physical	18782782
FBW1B_MOUSE	Fbxw11	physical	18782782

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.