BMAL1_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: BMAL1_HUMAN
• UniProt AC: O00327
• Protein Name: Aryl hydrocarbon receptor nuclear translocator-like protein 1
• Gene Name: ARNTL
• Organism: Homo sapiens (Human).
• Sequence Length: 626
• Subcellular Localization: Nucleus . Cytoplasm . Nucleus, PML body . Shuttles between the nucleus and the cytoplasm and this nucleocytoplasmic shuttling is essential for the nuclear accumulation of CLOCK, target gene transcription and the degradation of the CLOCK-ARNTL/BMAL1 h
• 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. ARNTL/BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. 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 NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. 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: MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSSTDYQESMDTDKDDPHGRLEYTEHQGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATNPYTEANYKPTFLSDDELKHLILRAADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKDFPSTCSKKKADRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHVVPQPVNGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVLANVLEGGDPTFPQLTASPHSMDSMLPSGEGGPKRTHPTVPGIPGGTRAGAGKIGRMIAEEIMEIHRIRGSSPSSCGSSPLNITSTPPPDASSPGGKKILNGGTPDIPSSGLLSGQAQENPGYPYSDSSSILGENPHIGIDMIDNDQGSSSPSNDEAAMAVIMSLLEADAGLGGPVDFSDLPWPL

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
6 (in isoform 1)	Phosphorylation	-	4.45	27794612
6 (in isoform 9)	Phosphorylation	-	4.45	27794612
9 (in isoform 1)	Phosphorylation	-	19.71	27794612
9 (in isoform 9)	Phosphorylation	-	19.71	27794612
17	Phosphorylation	STISDFMSPGPTDLL HHHHHHCCCCHHHHH	27.05	22817900
21	Phosphorylation	DFMSPGPTDLLSSSL HHCCCCHHHHHHHHC	45.23	22817900
35	Phosphorylation	LGTSGVDCNRKRKGS CCCCCCCCCCCCCCC	5.02	18077418
42	Phosphorylation	CNRKRKGSSTDYQES CCCCCCCCCCCHHHH	32.85	29496963
43	Phosphorylation	NRKRKGSSTDYQESM CCCCCCCCCCHHHHH	33.69	21815630
44	Phosphorylation	RKRKGSSTDYQESMD CCCCCCCCCHHHHHC	40.18	26657352
46	Phosphorylation	RKGSSTDYQESMDTD CCCCCCCHHHHHCCC	17.80	28985074
49	Phosphorylation	SSTDYQESMDTDKDD CCCCHHHHHCCCCCC	13.36	26657352
52	Phosphorylation	DYQESMDTDKDDPHG CHHHHHCCCCCCCCC	35.99	29449344
63	Phosphorylation	DPHGRLEYTEHQGRI CCCCCCCCHHHHHHH	23.24	-
78	Phosphorylation	KNAREAHSQIEKRRR CCHHHHHHHHHHHHH	39.64	26471730
90	Phosphorylation	RRRDKMNSFIDELAS HHHHHHHHHHHHHHH	21.78	-
101	Phosphorylation	ELASLVPTCNAMSRK HHHHHHHHHHHHHHH	15.77	30631047
106	Phosphorylation	VPTCNAMSRKLDKLT HHHHHHHHHHHHHHH	24.69	30631047
123	Ubiquitination	RMAVQHMKTLRGATN HHHHHHHHHHCCCCC	42.13	-
138	Ubiquitination	PYTEANYKPTFLSDD CCCHHCCCCCCCCHH	37.07	-
205	Ubiquitination	PKDIAKVKEQLSSSD HHHHHHHHHHHHCCC	38.75	-
223 (in isoform 3)	Ubiquitination	-	39.10	-
224	Phosphorylation	ERLIDAKTGLPVKTD HHHCCCCCCCCCCCC	45.75	-
259	Sumoylation	KCNRPSVKVEDKDFP CCCCCCCEECCCCCC	44.22	18644859
259	Sumoylation	KCNRPSVKVEDKDFP CCCCCCCEECCCCCC	44.22	-
263	Acetylation	PSVKVEDKDFPSTCS CCCEECCCCCCCCCC	48.00	26051181
281	Phosphorylation	ADRKSFCTIHSTGYL CCCCCCEEEECCCCC	21.51	28985074
284	Phosphorylation	KSFCTIHSTGYLKSW CCCEEEECCCCCCCC	21.48	28985074
285	Phosphorylation	SFCTIHSTGYLKSWP CCEEEECCCCCCCCC	18.71	28985074
294	Phosphorylation	YLKSWPPTKMGLDED CCCCCCCCCCCCCCC	29.59	-
398	Ubiquitination	QVLQTREKITTNCYK HHHHCHHHHCCCEEE	41.90	-
400	Phosphorylation	LQTREKITTNCYKFK HHCHHHHCCCEEEEE	24.03	26657352
401	Phosphorylation	QTREKITTNCYKFKI HCHHHHCCCEEEEEE	27.11	26657352
404	Phosphorylation	EKITTNCYKFKIKDG HHHCCCEEEEEECCC	22.87	26657352
409	Ubiquitination	NCYKFKIKDGSFITL CEEEEEECCCCEEEE	57.54	-
418	O-linked_Glycosylation	GSFITLRSRWFSFMN CCEEEEEECEEHHCC	36.66	23395176
477	Phosphorylation	GEGGPKRTHPTVPGI CCCCCCCCCCCCCCC	38.03	27251275
480	Phosphorylation	GPKRTHPTVPGIPGG CCCCCCCCCCCCCCC	31.56	27251275
488	Phosphorylation	VPGIPGGTRAGAGKI CCCCCCCCCCCCHHH	24.22	28674419
494	Acetylation	GTRAGAGKIGRMIAE CCCCCCHHHHHHHHH	41.26	25953088
512	Phosphorylation	EIHRIRGSSPSSCGS HHHCCCCCCCCCCCC	29.27	28348404
513	Phosphorylation	IHRIRGSSPSSCGSS HHCCCCCCCCCCCCC	31.46	24719451
515	Phosphorylation	RIRGSSPSSCGSSPL CCCCCCCCCCCCCCC	39.96	28348404
516	Phosphorylation	IRGSSPSSCGSSPLN CCCCCCCCCCCCCCC	26.36	28348404
519	Phosphorylation	SSPSSCGSSPLNITS CCCCCCCCCCCCCCC	32.86	28348404
520	Phosphorylation	SPSSCGSSPLNITST CCCCCCCCCCCCCCC	20.77	28348404
527	Phosphorylation	SPLNITSTPPPDASS CCCCCCCCCCCCCCC	31.03	28985074
534	Phosphorylation	TPPPDASSPGGKKIL CCCCCCCCCCCCCCC	29.32	28985074
538	Acetylation	DASSPGGKKILNGGT CCCCCCCCCCCCCCC	42.42	26051181
592	Phosphorylation	DNDQGSSSPSNDEAA CCCCCCCCCCHHHHH	33.76	-

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
17	S	Phosphorylation	Kinase	GSK3B	P49841	PSP
21	T	Phosphorylation	Kinase	GSK3B	P49841	PSP
90	S	Phosphorylation	Kinase	CSNK2A1	P68400	GPS
90	S	Phosphorylation	Kinase	CK2	-	Uniprot
520	S	Phosphorylation	Kinase	MAPK8	Q91Y86	GPS
520	S	Phosphorylation	Kinase	MAPK9	Q9WTU6	GPS
527	T	Phosphorylation	Kinase	MAPK8	Q91Y86	GPS
527	T	Phosphorylation	Kinase	MAPK9	Q9WTU6	GPS
592	S	Phosphorylation	Kinase	MAPK8	Q91Y86	GPS
592	S	Phosphorylation	Kinase	MAPK9	Q9WTU6	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	UBE3A	Q05086	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	STUB1	Q9UNE7	PMID:32041778

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
78	S	Phosphorylation	Dephosphorylation at Ser-78 is important for dimerization with CLOCK and transcriptional activity.	23229515
90	S	Phosphorylation	Phosphorylation at Ser-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry (By similarity).	23229515
259	K	Sumoylation	Sumoylated on Lys-259 upon dimerization with CLOCK.	28112733
538	K	Acetylation	Acetylated on Lys-538 upon dimerization with CLOCK.	-

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of BMAL1_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CRY1_HUMAN	CRY1	physical	10531061
NPAS2_HUMAN	NPAS2	physical	11439184
CLOCK_HUMAN	CLOCK	physical	11439184
AHR_HUMAN	AHR	physical	9079689
NPAS2_HUMAN	NPAS2	physical	9576906
EPAS1_HUMAN	EPAS1	physical	9576906
HIF1A_HUMAN	HIF1A	physical	9576906
CLOCK_HUMAN	CLOCK	physical	9576906
CLOCK_HUMAN	CLOCK	physical	19922678
UBE3A_HUMAN	UBE3A	physical	24728990
HIF1A_HUMAN	HIF1A	physical	25416956
CLOCK_HUMAN	CLOCK	physical	23555304
CRY1_HUMAN	CRY1	physical	23555304
CRY2_HUMAN	CRY2	physical	23555304
CSK2B_HUMAN	CSNK2B	physical	23555304
DEC1_HUMAN	DEC1	physical	23555304
NPAS2_HUMAN	NPAS2	physical	23555304
WDR5_HUMAN	WDR5	physical	23555304
RORG_HUMAN	RORC	physical	23555304
KC1E_HUMAN	CSNK1E	physical	23555304
UBE3A_HUMAN	UBE3A	physical	25660546
CLOCK_HUMAN	CLOCK	physical	28514442
BCAM_HUMAN	BCAM	physical	28514442
BMAL2_HUMAN	ARNTL2	physical	28514442
NPAS2_HUMAN	NPAS2	physical	28514442
LRFN4_HUMAN	LRFN4	physical	28514442
RPR1A_HUMAN	RPRD1A	physical	27173435
CAVN1_HUMAN	PTRF	physical	27173435
VPS50_HUMAN	CCDC132	physical	27173435
PSMD9_HUMAN	PSMD9	physical	27173435
CLOCK_HUMAN	CLOCK	physical	27173435
YETS4_HUMAN	YEATS4	physical	27173435
TFPT_HUMAN	TFPT	physical	27173435
PKN3_HUMAN	PKN3	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.