dbPTM

CLOCK_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	CLOCK_HUMAN
UniProt AC	O15516
Protein Name	Circadian locomoter output cycles protein kaput
Gene Name	CLOCK
Organism	Homo sapiens (Human).
Sequence Length	846
Subcellular Localization	Nucleus . Cytoplasm . Cytoplasm, cytosol . Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1-dependent. Phosphorylated form located in the nucleus while the nonphosphorylated form found only in the cytop
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. 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. [PubMed: 23229515 CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3']
Protein Sequence	MLFTVSCSKMSSIVDRDDSSIFDGLVEEDDKDKAKRVSRNKSEKKRRDQFNVLIKELGSMLPGNARKMDKSTVLQKSIDFLRKHKEITAQSDASEIRQDWKPTFLSNEEFTQLMLEALDGFFLAIMTDGSIIYVSESVTSLLEHLPSDLVDQSIFNFIPEGEHSEVYKILSTHLLESDSLTPEYLKSKNQLEFCCHMLRGTIDPKEPSTYEYVKFIGNFKSLNSVSSSAHNGFEGTIQRTHRPSYEDRVCFVATVRLATPQFIKEMCTVEEPNEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHVDDLENLAKCHEHLMQYGKGKSCYYRFLTKGQQWIWLQTHYYITYHQWNSRPEFIVCTHTVVSYAEVRAERRRELGIEESLPETAADKSQDSGSDNRINTVSLKEALERFDHSPTPSASSRSSRKSSHTAVSDPSSTPTKIPTDTSTPPRQHLPAHEKMVQRRSSFSSQSINSQSVGSSLTQPVMSQATNLPIPQGMSQFQFSAQLGAMQHLKDQLEQRTRMIEANIHRQQEELRKIQEQLQMVHGQGLQMFLQQSNPGLNFGSVQLSSGNSSNIQQLAPINMQGQVVPTNQIQSGMNTGHIGTTQHMIQQQTLQSTSTQSQQNVLSGHSQQTSLPSQTQSTLTAPLYNTMVISQPAAGSMVQIPSSMPQNSTQSAAVTTFTQDRQIRFSQGQQLVTKLVTAPVACGAVMVPSTMLMGQVVTAYPTFATQQQQSQTLSVTQQQQQQSSQEQQLTSVQQPSQAQLTQPPQQFLQTSRLLHGNPSTQLILSAAFPLQQSTFPQSHHQQHQSQQQQQLSRHRTDSLPDPSKVQPQ

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
8	Phosphorylation	MLFTVSCSKMSSIVD CCEEEECCHHHHCCC	24.72	30631047
19	Phosphorylation	SIVDRDDSSIFDGLV HCCCCCCCCCCCCCC	29.62	27732954
20	Phosphorylation	IVDRDDSSIFDGLVE CCCCCCCCCCCCCCC	33.98	27732954
31	Acetylation	GLVEEDDKDKAKRVS CCCCCCCHHHHHHHH	73.73	20167786
38	Phosphorylation	KDKAKRVSRNKSEKK HHHHHHHHCCHHHHH	33.88	-
41	Acetylation	AKRVSRNKSEKKRRD HHHHHCCHHHHHHHH	59.90	20167786
42	Phosphorylation	KRVSRNKSEKKRRDQ HHHHCCHHHHHHHHH	59.19	-
59	Phosphorylation	VLIKELGSMLPGNAR HHHHHHHHCCCCCHH	29.75	-
67	Sumoylation	MLPGNARKMDKSTVL CCCCCHHCCCHHHHH	49.38	-
67	Sumoylation	MLPGNARKMDKSTVL CCCCCHHCCCHHHHH	49.38	-
76	Ubiquitination	DKSTVLQKSIDFLRK CHHHHHHHHHHHHHH	45.26	-
85	Ubiquitination	IDFLRKHKEITAQSD HHHHHHCHHHHCCCC	54.57	21906983
88	Phosphorylation	LRKHKEITAQSDASE HHHCHHHHCCCCHHH	21.53	25954137
164	Phosphorylation	FIPEGEHSEVYKILS CCCCCCCHHHHHHHH	25.18	-
177	Phosphorylation	LSTHLLESDSLTPEY HHHHHHHCCCCCHHH	32.25	27067055
179	Phosphorylation	THLLESDSLTPEYLK HHHHHCCCCCHHHHH	43.34	27251275
186	Ubiquitination	SLTPEYLKSKNQLEF CCCHHHHHCCCHHHH	59.49	21906983
205	Ubiquitination	LRGTIDPKEPSTYEY HCCCCCCCCCCHHHE	77.75	-
331	Phosphorylation	CHEHLMQYGKGKSCY HHHHHHHHCCCCCCE	13.57	27273156
394	Phosphorylation	RELGIEESLPETAAD HHCCCCCCCCCCCCC	36.11	25072903
398	Phosphorylation	IEESLPETAADKSQD CCCCCCCCCCCCCCC	25.80	25072903
402	Ubiquitination	LPETAADKSQDSGSD CCCCCCCCCCCCCCC	45.34	21906983
403	Phosphorylation	PETAADKSQDSGSDN CCCCCCCCCCCCCCC	39.50	23663014
406	Phosphorylation	AADKSQDSGSDNRIN CCCCCCCCCCCCCCC	32.34	30266825
408	Phosphorylation	DKSQDSGSDNRINTV CCCCCCCCCCCCCEE	35.35	23663014
414	Phosphorylation	GSDNRINTVSLKEAL CCCCCCCEECHHHHH	14.75	25072903
416	Phosphorylation	DNRINTVSLKEALER CCCCCEECHHHHHHH	31.52	23090842
418	Ubiquitination	RINTVSLKEALERFD CCCEECHHHHHHHCC	33.17	2190698
427	Phosphorylation	ALERFDHSPTPSASS HHHHCCCCCCCCCCC	32.11	30266825
429	Phosphorylation	ERFDHSPTPSASSRS HHCCCCCCCCCCCCC	32.65	30266825
431	Phosphorylation	FDHSPTPSASSRSSR CCCCCCCCCCCCCCC	43.17	30266825
433	Phosphorylation	HSPTPSASSRSSRKS CCCCCCCCCCCCCCC	30.53	23403867
434	Phosphorylation	SPTPSASSRSSRKSS CCCCCCCCCCCCCCC	35.58	23403867
437	Phosphorylation	PSASSRSSRKSSHTA CCCCCCCCCCCCCCC	42.49	22817900
440	Phosphorylation	SSRSSRKSSHTAVSD CCCCCCCCCCCCCCC	26.66	28985074
441	Phosphorylation	SRSSRKSSHTAVSDP CCCCCCCCCCCCCCC	28.08	25849741
443	Phosphorylation	SSRKSSHTAVSDPSS CCCCCCCCCCCCCCC	30.60	23927012
446	Phosphorylation	KSSHTAVSDPSSTPT CCCCCCCCCCCCCCC	41.14	25849741
449	Phosphorylation	HTAVSDPSSTPTKIP CCCCCCCCCCCCCCC	52.41	25159151
450	Phosphorylation	TAVSDPSSTPTKIPT CCCCCCCCCCCCCCC	43.74	23927012
451	Phosphorylation	AVSDPSSTPTKIPTD CCCCCCCCCCCCCCC	39.04	23927012
453	Phosphorylation	SDPSSTPTKIPTDTS CCCCCCCCCCCCCCC	41.51	23090842
457	Phosphorylation	STPTKIPTDTSTPPR CCCCCCCCCCCCCCH	56.22	30266825
459	Phosphorylation	PTKIPTDTSTPPRQH CCCCCCCCCCCCHHC	36.66	30266825
460	Phosphorylation	TKIPTDTSTPPRQHL CCCCCCCCCCCHHCC	41.55	30266825
461	Phosphorylation	KIPTDTSTPPRQHLP CCCCCCCCCCHHCCC	39.13	30266825
702	Dimethylation	FTQDRQIRFSQGQQL CCCCCEEEECHHHHH	19.47	-
702	Methylation	FTQDRQIRFSQGQQL CCCCCEEEECHHHHH	19.47	-
704	Phosphorylation	QDRQIRFSQGQQLVT CCCEEEECHHHHHHH	24.45	28555341
711	O-linked_Glycosylation	SQGQQLVTKLVTAPV CHHHHHHHHHHHCCC	27.53	23395176
836	Phosphorylation	LSRHRTDSLPDPSKV HHHHCCCCCCCHHHC	40.98	26657352
842	Sumoylation	DSLPDPSKVQPQ--- CCCCCHHHCCCC---	50.72	-
842	Sumoylation	DSLPDPSKVQPQ--- CCCCCHHHCCCC---	50.72	-

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	GSK3B	P49841	PSP
451	T	Phosphorylation	Kinase	CDK5	Q00535	Uniprot
461	T	Phosphorylation	Kinase	CDK5	Q00535	Uniprot

Functions of PTM Sites

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

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
BMAL1_HUMAN	ARNTL	physical	14701734
BMAL2_HUMAN	ARNTL2	physical	14701734
BMAL1_HUMAN	ARNTL	physical	11439184
RARA_HUMAN	RARA	physical	11439184
BMAL1_HUMAN	ARNTL	physical	20551151
CRY1_HUMAN	CRY1	physical	23555304
CRY2_HUMAN	CRY2	physical	23555304
DEC1_HUMAN	DEC1	physical	23555304
BHE41_HUMAN	BHLHE41	physical	23555304
NPAS2_HUMAN	NPAS2	physical	23555304
2A5D_HUMAN	PPP2R5D	physical	23555304
2A5E_HUMAN	PPP2R5E	physical	23555304
CSK2B_HUMAN	CSNK2B	physical	23555304
2AAB_HUMAN	PPP2R1B	physical	23555304
NR1D2_HUMAN	NR1D2	physical	23555304
PER2_HUMAN	PER2	physical	23555304
PP1A_HUMAN	PPP1CA	physical	23555304
PP1B_HUMAN	PPP1CB	physical	23555304
PP1G_HUMAN	PPP1CC	physical	23555304
KC1E_HUMAN	CSNK1E	physical	23555304
DBP_HUMAN	DBP	physical	23555304
RORG_HUMAN	RORC	physical	23555304
BMAL1_HUMAN	ARNTL	physical	26164627
PKN3_HUMAN	PKN3	physical	27173435
VPS50_HUMAN	CCDC132	physical	27173435
CAVN1_HUMAN	PTRF	physical	27173435
RPR1A_HUMAN	RPRD1A	physical	27173435
RABX5_HUMAN	RABGEF1	physical	27173435

Drug and Disease Associations

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

Regulatory Network of CLOCK_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"An extensive survey of tyrosine phosphorylation revealing new sitesin human mammary epithelial cells."; Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A.,Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D.,Wiley H.S., Qian W.-J.; J. Proteome Res. 8:3852-3861(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-331, AND MASSSPECTROMETRY.	19534553 [Abstract]