dbPTM

BMAL1_MOUSE - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	BMAL1_MOUSE
UniProt AC	Q9WTL8
Protein Name	Aryl hydrocarbon receptor nuclear translocator-like protein 1
Gene Name	Arntl
Organism	Mus musculus (Mouse).
Sequence Length	632
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. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. 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 (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' (By similarity). Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1. [PubMed: 28985504]
Protein Sequence	MADQRMDISSTISDFMSPGPTDLLSGSLGTSGVDCNRKRKGSATDYQLDDFAFEESMDTDKDDPHGRLEYAEHQGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATNPYTEANYKPTFLSDDELKHLILRAADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKDFASTCSKKKDRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHMVPQPANGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVLANVLEGGDPTFPQLTAPPHSMDSMLPSGEGGPKRTHPTVPGIPGGTRAGAGKIGRMIAEEIMEIHRIRGSSPSSCGSSPLNITSTPPPDASSPGGKKILNGGTPDIPSTGLLPGQAQETPGYPYSDSSSILGENPHIGIDMIDNDQGSSSPSNDEAAMAVIMSLLEADAGLGGPVDFSDLPWPL

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
17	Phosphorylation	STISDFMSPGPTDLL HHHHHHCCCCCCCCC	27.05	20049328
21	Phosphorylation	DFMSPGPTDLLSGSL HHCCCCCCCCCCCCC	45.23	20049328
42 (in isoform 5)	Phosphorylation	-	30.91	27742792
42 (in isoform 2)	Phosphorylation	-	30.91	27742792
42	Phosphorylation	CNRKRKGSATDYQLD CCCCCCCCCCCCCCC	30.91	20469934
42 (in isoform 4)	Phosphorylation	-	30.91	27742792
44 (in isoform 2)	Phosphorylation	-	36.62	27742792
44 (in isoform 5)	Phosphorylation	-	36.62	27742792
44 (in isoform 4)	Phosphorylation	-	36.62	27742792
46 (in isoform 5)	Phosphorylation	-	13.45	27742792
46 (in isoform 2)	Phosphorylation	-	13.45	27742792
46 (in isoform 4)	Phosphorylation	-	13.45	27742792
49 (in isoform 5)	Phosphorylation	-	33.19	29550500
49 (in isoform 2)	Phosphorylation	-	33.19	29550500
49 (in isoform 4)	Phosphorylation	-	33.19	29550500
52 (in isoform 5)	Phosphorylation	-	20.24	29550500
52 (in isoform 2)	Phosphorylation	-	20.24	29550500
52 (in isoform 4)	Phosphorylation	-	20.24	29550500
85	Phosphorylation	KNAREAHSQIEKRRR CCHHHHHHHHHHHHH	39.64	-
90 (in isoform 4)	Phosphorylation	-	26.52	-
97	Phosphorylation	RRRDKMNSFIDELAS HHHHHHHHHHHHHHH	21.78	19330005
248	Phosphorylation	PGPSRLCSGARRSFF CCCCCCCCCCCCHHE	39.83	21454597
259	Ubiquitination	RSFFCRMKCNRPSVK CHHEEEECCCCCCCE	14.70	PubMed
259	Sumoylation	RSFFCRMKCNRPSVK CHHEEEECCCCCCCE	14.70	18644859
266	Sumoylation	KCNRPSVKVEDKDFA CCCCCCCEECCCCHH	44.22	16109848
266	Sumoylation	KCNRPSVKVEDKDFA CCCCCCCEECCCCHH	44.22	-
300	Phosphorylation	YLKSWPPTKMGLDED CCCCCCCCCCCCCCC	29.59	-
343	Phosphorylation	NGEIRVKSMEYVSRH CCCEEEEEEEEEEHH	17.62	22802335
418	O-linked_Glycosylation	KFKIKDGSFITLRSR EEEECCCCEEEEEEC	24.49	-
500	Acetylation	GTRAGAGKIGRMIAE CCCCCCHHHHHHHHH	41.26	23806337
518	Phosphorylation	EIHRIRGSSPSSCGS HHHCCCCCCCCCCCC	29.27	21082442
522	Phosphorylation	IRGSSPSSCGSSPLN CCCCCCCCCCCCCCC	26.36	22871156
531	Phosphorylation	GSSPLNITSTPPPDA CCCCCCCCCCCCCCC	26.02	22871156
533	Phosphorylation	SPLNITSTPPPDASS CCCCCCCCCCCCCCC	31.03	21082442
538 (in isoform 4)	Acetylation	-	20.06	-
544	Acetylation	DASSPGGKKILNGGT CCCCCCCCCCCCCCC	42.42	18075593

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	GSK3-BETA	Q9WV60	Uniprot
21	T	Phosphorylation	Kinase	GSK3-BETA	Q9WV60	Uniprot
90	S	Phosphorylation	Kinase	CSNK2A1	Q60737	GPS
97	S	Phosphorylation	Kinase	CK2A1	P68400	PSP
97	S	Phosphorylation	Kinase	CSNK2A1	Q60737	GPS
97	S	Phosphorylation	Kinase	CK2	-	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
85	S	Phosphorylation	11779462
Dephosphorylation at Ser-85 is important for dimerization with CLOCK and transcriptional activity (By similarity).
97	S	Phosphorylation	19330005
Phosphorylation at Ser-97 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry.
266	K	Sumoylation	16109848
Sumoylated on Lys-266 upon dimerization with CLOCK.
544	K	Acetylation	18075593
Acetylated on Lys-544 upon dimerization with CLOCK.

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 BMAL1_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CLOCK_MOUSE	Clock	physical	14701732
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
EPAS1_MOUSE	Epas1	physical	20211142
HIF1A_MOUSE	Hif1a	physical	20211142
RNF14_MOUSE	Rnf14	physical	20211142
CLOCK_MOUSE	Clock	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
CRY1_MOUSE	Cry1	physical	21966515
KC1E_MOUSE	Csnk1e	physical	21966515
UBP2_MOUSE	Usp2	physical	21966515
HIF1A_MOUSE	Hif1a	physical	9704006
CLOCK_MOUSE	Clock	physical	9704006
HIF1A_HUMAN	HIF1A	physical	9704006
UBP2_MOUSE	Usp2	physical	23213472

Drug and Disease Associations

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

Regulatory Network of BMAL1_MOUSE

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"CLOCK-mediated acetylation of BMAL1 controls circadian function."; Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K.,Nakahata Y., Sassone-Corsi P.; Nature 450:1086-1090(2007). Cited for: ACETYLATION AT LYS-544.	18075593 [Abstract]
Sumoylation
Reference	PubMed
"Circadian clock control by SUMOylation of BMAL1."; Cardone L., Hirayama J., Giordano F., Tamaru T., Palvimo J.J.,Sassone-Corsi P.; Science 309:1390-1394(2005). Cited for: SUMOYLATION AT LYS-266, AND MUTAGENESIS OF LYS-230; LYS-236; LYS-266AND LYS-279.	16109848 [Abstract]

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