CLOCK_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CLOCK_MOUSE
• UniProt AC: O08785
• Protein Name: Circadian locomoter output cycles protein kaput
• Gene Name: Clock
• Organism: Mus musculus (Mouse).
• Sequence Length: 855
• Subcellular Localization: Nucleus . Cytoplasm . Cytoplasm, cytosol . Localizes to sites of DNA damage in a H2AX-independent manner (By similarity). Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1-dependent. Phosphorylated form
• Protein Description: Transcriptional activator 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 syndromes 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. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner (By similarity). Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis. [PubMed: 28985504]
• Protein Sequence: MVFTVSCSKMSSIVDRDDSSIFDGLVEEDDKDKAKRVSRNKSEKKRRDQFNVLIKELGSMLPGNARKMDKSTVLQKSIDFLRKHKETTAQSDASEIRQDWKPTFLSNEEFTQLMLEALDGFFLAIMTDGSIIYVSESVTSLLEHLPSDLVDQSIFNFIPEGEHSEVYKILSTHLLESDSLTPEYLKSKNQLEFCCHMLRGTIDPKEPSTYEYVRFIGNFKSLTSVSTSTHNGFEGTIQRTHRPSYEDRVCFVATVRLATPQFIKEMCTVEEPNEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHVDDLENLAKCHEHLMQYGKGKSCYYRFLTKGQQWIWLQTHYYITYHQWNSRPEFIVCTHTVVSYAEVRAERRRELGIEESLPETAADKSQDSGSDNRINTVSLKEALERFDHSPTPSASSRSSRKSSHTAVSDPSSTPTKIPTDTSTPPRQHLPAHEKMTQRRSSFSSQSINSQSVGPSLTQPAMSQAANLPIPQGMSQFQFSAQLGAMQHLKDQLEQRTRMIEANIHRQQEELRKIQEQLQMVHGQGLQMFLQQSNPGLNFGSVQLSSGNSNIQQLTPVNMQGQVVPANQVQSGHISTGQHMIQQQTLQSTSTQQSQQSVMSGHSQQTSLPSQTPSTLTAPLYNTMVISQPAAGSMVQIPSSMPQNSTQSATVTTFTQDRQIRFSQGQQLVTKLVTAPVACGAVMVPSTMLMGQVVTAYPTFATQQQQAQTLSVTQQQQQQQQQPPQQQQQQQQSSQEQQLPSVQQPAQAQLGQPPQQFLQTSRLLHGNPSTQLILSAAFPLQQSTFPPSHHQQHQPQQQQQLPRHRTDSLTDPSKVQPQ

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
20	Phosphorylation	IVDRDDSSIFDGLVE HCCCCCCCCCCCCCC	33.98	26370283
38	Phosphorylation	KDKAKRVSRNKSEKK HHHHHHHHCCHHHHH	33.88	19414601
42	Phosphorylation	KRVSRNKSEKKRRDQ HHHHCCHHHHHHHHH	59.19	19414601
67	Sumoylation	MLPGNARKMDKSTVL CCCCCHHCCCHHHHH	49.38	23160374
186	Ubiquitination	SLTPEYLKSKNQLEF CCCHHHHHCCCHHHH	59.49	-
331	Phosphorylation	CHEHLMQYGKGKSCY HHHHHHHHCCCCCCE	13.57	25195567
372	Phosphorylation	RPEFIVCTHTVVSYA CCCEEEEEEEEEEHH	15.08	21454597
378	Phosphorylation	CTHTVVSYAEVRAER EEEEEEEHHHHHHHH	8.65	21454597
403	Phosphorylation	PETAADKSQDSGSDN CCCCCCCCCCCCCCC	39.50	22324799
406	Phosphorylation	AADKSQDSGSDNRIN CCCCCCCCCCCCCCC	32.34	22324799
408	Phosphorylation	DKSQDSGSDNRINTV CCCCCCCCCCCCCEE	35.35	22324799
414	Phosphorylation	GSDNRINTVSLKEAL CCCCCCCEECHHHHH	14.75	22324799
416	Phosphorylation	DNRINTVSLKEALER CCCCCEECHHHHHHH	31.52	22324799
427	Phosphorylation	ALERFDHSPTPSASS HHHHCCCCCCCCCCC	32.11	26824392
429	Phosphorylation	ERFDHSPTPSASSRS HHCCCCCCCCCCCCC	32.65	28066266
431	Phosphorylation	FDHSPTPSASSRSSR CCCCCCCCCCCCCCC	43.17	19946213
440	Phosphorylation	SSRSSRKSSHTAVSD CCCCCCCCCCCCCCC	26.66	23684622
441	Phosphorylation	SRSSRKSSHTAVSDP CCCCCCCCCCCCCCC	28.08	23684622
443	Phosphorylation	SSRKSSHTAVSDPSS CCCCCCCCCCCCCCC	30.60	25521595
446	Phosphorylation	KSSHTAVSDPSSTPT CCCCCCCCCCCCCCC	41.14	23684622
449	Phosphorylation	HTAVSDPSSTPTKIP CCCCCCCCCCCCCCC	52.41	29472430
450	Phosphorylation	TAVSDPSSTPTKIPT CCCCCCCCCCCCCCC	43.74	29472430
451	Phosphorylation	AVSDPSSTPTKIPTD CCCCCCCCCCCCCCC	39.04	29472430
453	Phosphorylation	SDPSSTPTKIPTDTS CCCCCCCCCCCCCCC	41.51	29472430
457	Phosphorylation	STPTKIPTDTSTPPR CCCCCCCCCCCCCCH	56.22	26643407
459	Phosphorylation	PTKIPTDTSTPPRQH CCCCCCCCCCCCHHC	36.66	26643407
460	Phosphorylation	TKIPTDTSTPPRQHL CCCCCCCCCCCHHCC	41.55	26643407
461	Phosphorylation	KIPTDTSTPPRQHLP CCCCCCCCCCHHCCC	39.13	23160374
698	Dimethylation	FTQDRQIRFSQGQQL ECCCCEEEECHHHHH	19.47	-
843	Phosphorylation	QQLPRHRTDSLTDPS HCCCCCCCCCCCCHH	24.66	29472430
845	Phosphorylation	LPRHRTDSLTDPSKV CCCCCCCCCCCHHHC	32.34	26824392
847	Phosphorylation	RHRTDSLTDPSKVQP CCCCCCCCCHHHCCC	50.22	25266776
850	Phosphorylation	TDSLTDPSKVQPQ-- CCCCCCHHHCCCC--	48.55	25777480
851	Sumoylation	DSLTDPSKVQPQ--- CCCCCHHHCCCC---	50.72	23160374

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
427	S	Phosphorylation	Kinase	GSK3-BETA	Q9WV60	Uniprot
451	T	Phosphorylation	Kinase	CDK5	P49615	Uniprot
461	T	Phosphorylation	Kinase	CDK5	P49615	Uniprot
843	T	Phosphorylation	Kinase	MAP3K5	O35099	GPS
845	S	Phosphorylation	Kinase	AKT1	P31749	PSP
845	S	Phosphorylation	Kinase	MAP3K5	O35099	GPS

Functions of PTM Sites

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

Disease-associated PTM Sites based on SAP

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

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

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
PER1_MOUSE	Per1	physical	14701732
PER2_MOUSE	Per2	physical	14701732
PER3_MOUSE	Per3	physical	14701732
CRY1_MOUSE	Cry1	physical	14701732
CRY2_MOUSE	Cry2	physical	14701732
TIM_HUMAN	TIMELESS	genetic	9856465
PER1_MOUSE	Per1	genetic	9856465
BMAL1_MOUSE	Arntl	physical	16717091
EZH2_MOUSE	Ezh2	physical	16717091
PER1_MOUSE	Per1	physical	16717091
PER2_MOUSE	Per2	physical	16717091
CRY1_MOUSE	Cry1	physical	16717091
CRY2_MOUSE	Cry2	physical	16717091
DBP_MOUSE	Dbp	physical	21113167
PER2_MOUSE	Per2	physical	21113167
KAT2B_MOUSE	Kat2b	physical	16678094
KAT5_MOUSE	Kat5	physical	16678094
BMAL1_MOUSE	Arntl	physical	16606840
CRY1_MOUSE	Cry1	physical	18662546
BMAL1_MOUSE	Arntl	physical	18662546
PER2_MOUSE	Per2	physical	18662546

Drug and Disease Associations

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

Related Literatures of Post-Translational Modification

Phosphorylation

"Large-scale phosphorylation analysis of mouse liver.";
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-408, AND MASSSPECTROMETRY.
PubMed: 17242355