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Protein

Aryl hydrocarbon receptor nuclear translocator-like protein 2

Gene

ARNTL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.3 Publications

GO - Molecular functioni

GO - Biological processi

  • circadian rhythm Source: MGI
  • entrainment of circadian clock Source: UniProtKB
  • positive regulation of circadian rhythm Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription by RNA polymerase II Source: BHF-UCL
  • regulation of transcription, DNA-templated Source: UniProtKB
  • regulation of transcription by RNA polymerase II Source: MGI
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionActivator, DNA-binding
Biological processBiological rhythms, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1368108 BMAL1:CLOCK,NPAS2 activates circadian gene expression
SIGNORiQ8WYA1

Names & Taxonomyi

Protein namesi
Recommended name:
Aryl hydrocarbon receptor nuclear translocator-like protein 2
Alternative name(s):
Basic-helix-loop-helix-PAS protein MOP9
Brain and muscle ARNT-like 2
CYCLE-like factor
Short name:
CLIF
Class E basic helix-loop-helix protein 6
Short name:
bHLHe6
Member of PAS protein 9
PAS domain-containing protein 9
Gene namesi
Name:ARNTL2
Synonyms:BHLHE6, BMAL2, CLIF, MOP9, PASD9
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000029153.14
HGNCiHGNC:18984 ARNTL2
MIMi614517 gene
neXtProtiNX_Q8WYA1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi56938
OpenTargetsiENSG00000029153
PharmGKBiPA134896555

Polymorphism and mutation databases

BioMutaiARNTL2
DMDMi124007121

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002736311 – 636Aryl hydrocarbon receptor nuclear translocator-like protein 2Add BLAST636

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki287Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2 and SUMO3)By similarity
Cross-linki294Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Keywords - PTMi

Isopeptide bond, Ubl conjugation

Proteomic databases

EPDiQ8WYA1
MaxQBiQ8WYA1
PaxDbiQ8WYA1
PeptideAtlasiQ8WYA1
PRIDEiQ8WYA1
ProteomicsDBi75143
75144 [Q8WYA1-2]
75145 [Q8WYA1-3]
75146 [Q8WYA1-4]
75147 [Q8WYA1-5]
75148 [Q8WYA1-6]
75149 [Q8WYA1-7]
75150 [Q8WYA1-8]

PTM databases

iPTMnetiQ8WYA1
PhosphoSitePlusiQ8WYA1

Expressioni

Tissue specificityi

Expressed in fetal brain. Highly expressed in brain and placenta. Lower levels in heart, liver, thymus, kidney and lung. Located to endothelial cells and neuronal cells of the suprachiasmatic nucleus (SCN). Also detected in endothelial cells of the heart, lung and kidney. In the brain, specifically expressed in the thalamus, hippocampus and amygdala.3 Publications

Inductioni

Constitutively expressed. Has no circadian rhythm expression pattern.1 Publication

Gene expression databases

BgeeiENSG00000029153
CleanExiHS_ARNTL2
ExpressionAtlasiQ8WYA1 baseline and differential
GenevisibleiQ8WYA1 HS

Organism-specific databases

HPAiHPA059074
HPA065355

Interactioni

Subunit structurei

Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with CLOCK to form the ARNTL2/BMAL2-CLOCK transactivator. Can form heterodimers or homodimers which interact directly with CLOCK to form the transcription activator. Interacts with NPAS2 and HIF1A. Interacts with PER2 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
NPAS2Q997434EBI-12268276,EBI-3932727

GO - Molecular functioni

Protein-protein interaction databases

BioGridi121263, 23 interactors
ComplexPortaliCPX-3230 CLOCK-BMAL2 transcription complex
IntActiQ8WYA1, 7 interactors
STRINGi9606.ENSP00000266503

Structurei

Secondary structure

1636
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi368 – 375Combined sources8
Beta strandi379 – 384Combined sources6
Helixi387 – 391Combined sources5
Turni396 – 398Combined sources3
Turni404 – 407Combined sources4
Beta strandi410 – 412Combined sources3
Helixi413 – 424Combined sources12
Beta strandi426 – 428Combined sources3
Beta strandi430 – 438Combined sources9
Beta strandi440 – 442Combined sources3
Beta strandi444 – 455Combined sources12
Beta strandi458 – 460Combined sources3
Beta strandi462 – 470Combined sources9

3D structure databases

ProteinModelPortaliQ8WYA1
SMRiQ8WYA1
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini107 – 160bHLHPROSITE-ProRule annotationAdd BLAST54
Domaini178 – 250PAS 1PROSITE-ProRule annotationAdd BLAST73
Domaini357 – 427PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini432 – 475PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni46 – 258Interaction with PER2By similarityAdd BLAST213

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi49 – 54Nuclear localization signalBy similarity6
Motifi177 – 187Nuclear export signal 1By similarityAdd BLAST11
Motifi392 – 400Nuclear export signal 2By similarity9

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3561 Eukaryota
ENOG410XRJI LUCA
GeneTreeiENSGT00760000118788
HOGENOMiHOG000234379
HOVERGENiHBG107503
InParanoidiQ8WYA1
KOiK09099
OMAiSAMIPQC
OrthoDBiEOG091G126J
PhylomeDBiQ8WYA1
TreeFamiTF319983

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
PfamiView protein in Pfam
PF00010 HLH, 1 hit
PF00989 PAS, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 3 hits
TIGRFAMsiTIGR00229 sensory_box, 1 hit
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

Sequences (9)i

Sequence statusi: Complete.

This entry describes 9 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8WYA1-1) [UniParc]FASTAAdd to basket
Also known as: BMAL2a

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAAEEEAAAG GKVLREENQC IAPVVSSRVS PGTRPTAMGS FSSHMTEFPR
60 70 80 90 100
KRKGSDSDPS QSGIMTEKVV EKLSQNPLTY LLSTRIEISA SSGSRVEDGE
110 120 130 140 150
HQVKMKAFRE AHSQTEKRRR DKMNNLIEEL SAMIPQCNPM ARKLDKLTVL
160 170 180 190 200
RMAVQHLRSL KGLTNSYVGS NYRPSFLQDN ELRHLILKTA EGFLFVVGCE
210 220 230 240 250
RGKILFVSKS VSKILNYDQA SLTGQSLFDF LHPKDVAKVK EQLSSFDISP
260 270 280 290 300
REKLIDAKTG LQVHSNLHAG RTRVYSGSRR SFFCRIKSCK ISVKEEHGCL
310 320 330 340 350
PNSKKKEHRK FYTIHCTGYL RSWPPNIVGM EEERNSKKDN SNFTCLVAIG
360 370 380 390 400
RLQPYIVPQN SGEINVKPTE FITRFAVNGK FVYVDQRATA ILGYLPQELL
410 420 430 440 450
GTSCYEYFHQ DDHNNLTDKH KAVLQSKEKI LTDSYKFRAK DGSFVTLKSQ
460 470 480 490 500
WFSFTNPWTK ELEYIVSVNT LVLGHSEPGE ASFLPCSSQS SEESSRQSCM
510 520 530 540 550
SVPGMSTGTV LGAGSIGTDI ANEILDLQRL QSSSYLDDSS PTGLMKDTHT
560 570 580 590 600
VNCRSMSNKE LFPPSPSEMG ELEATRQNQS TVAVHSHEPL LSDGAQLDFD
610 620 630
ALCDNDDTAM AAFMNYLEAE GGLGDPGDFS DIQWTL
Length:636
Mass (Da):70,887
Last modified:January 23, 2007 - v2
Checksum:i972CE2BC5B05B1F3
GO
Isoform 2 (identifier: Q8WYA1-2) [UniParc]FASTAAdd to basket
Also known as: BMAL2b

The sequence of this isoform differs from the canonical sequence as follows:
     96-109: Missing.

Show »
Length:622
Mass (Da):69,231
Checksum:iEE042DBFFB87BC63
GO
Isoform 3 (identifier: Q8WYA1-3) [UniParc]FASTAAdd to basket
Also known as: BMAL2c

The sequence of this isoform differs from the canonical sequence as follows:
     11-11: G → GEVAGGEATAPG
     62-95: Missing.
     96-109: Missing.

Show »
Length:599
Mass (Da):66,493
Checksum:iA5B1B84DBC4B5B40
GO
Isoform 4 (identifier: Q8WYA1-4) [UniParc]FASTAAdd to basket
Also known as: BMAL2d

The sequence of this isoform differs from the canonical sequence as follows:
     62-95: Missing.
     96-109: Missing.

Show »
Length:588
Mass (Da):65,553
Checksum:i3D49ACC111064FD8
GO
Isoform 5 (identifier: Q8WYA1-5) [UniParc]FASTAAdd to basket
Also known as: CLIF

The sequence of this isoform differs from the canonical sequence as follows:
     62-95: Missing.

Show »
Length:602
Mass (Da):67,209
Checksum:iAD8937DD526D8B45
GO
Isoform 6 (identifier: Q8WYA1-6) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-37: Missing.
     62-95: Missing.
     96-109: Missing.

Show »
Length:551
Mass (Da):61,788
Checksum:iF845E3F54FFA39B0
GO
Isoform 7 (identifier: Q8WYA1-7) [UniParc]FASTAAdd to basket
Also known as: MOP9 long form

The sequence of this isoform differs from the canonical sequence as follows:
     1-37: Missing.
     96-109: Missing.

Show »
Length:585
Mass (Da):65,466
Checksum:iEE2E576065881B01
GO
Isoform 8 (identifier: Q8WYA1-8) [UniParc]FASTAAdd to basket
Also known as: MOP9 short form

The sequence of this isoform differs from the canonical sequence as follows:
     1-37: Missing.
     61-61: Q → H
     62-74: Missing.
     96-109: Missing.

Note: No experimental confirmation available.
Show »
Length:572
Mass (Da):64,072
Checksum:iFDDF781F6E2FDBC5
GO
Isoform 9 (identifier: Q8WYA1-9) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     11-11: G → GEVAGGEATAPG
     62-95: Missing.
     96-109: Missing.
     556-635: MSNKELFPPS...PGDFSDIQWT → VMVHSWISMPYVTMMTQPWLH

Note: No experimental confirmation available.
Show »
Length:540
Mass (Da):60,390
Checksum:i9C6DF2CB4CE1BB8A
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti41F → S in BAB01485 (PubMed:10964693).Curated1
Sequence conflicti173R → G in BAH12415 (PubMed:14702039).Curated1
Sequence conflicti257A → T in AAF71306 (PubMed:10864977).Curated1
Sequence conflicti257A → T in AAF71307 (PubMed:10864977).Curated1
Sequence conflicti276S → F in AAF71306 (PubMed:10864977).Curated1
Sequence conflicti276S → F in AAF71307 (PubMed:10864977).Curated1
Sequence conflicti304K → R in BAH12415 (PubMed:14702039).Curated1
Sequence conflicti324P → R in BAB01485 (PubMed:10964693).Curated1
Sequence conflicti527L → I in BAB01485 (PubMed:10964693).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_030158340N → S. Corresponds to variant dbSNP:rs1037921Ensembl.1
Natural variantiVAR_030159574A → V. Corresponds to variant dbSNP:rs11049005Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0225801 – 37Missing in isoform 6, isoform 7 and isoform 8. 2 PublicationsAdd BLAST37
Alternative sequenceiVSP_02258511G → GEVAGGEATAPG in isoform 3 and isoform 9. 3 Publications1
Alternative sequenceiVSP_02258261Q → H in isoform 8. 1 Publication1
Alternative sequenceiVSP_02258162 – 95Missing in isoform 3, isoform 4, isoform 5, isoform 6 and isoform 9. 5 PublicationsAdd BLAST34
Alternative sequenceiVSP_02258362 – 74Missing in isoform 8. 1 PublicationAdd BLAST13
Alternative sequenceiVSP_02258496 – 109Missing in isoform 2, isoform 3, isoform 4, isoform 6, isoform 7, isoform 8 and isoform 9. 5 PublicationsAdd BLAST14
Alternative sequenceiVSP_044773556 – 635MSNKE…DIQWT → VMVHSWISMPYVTMMTQPWL H in isoform 9. 1 PublicationAdd BLAST80

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB039921 mRNA Translation: BAB01485.1
AF256215 mRNA Translation: AAG34652.1
AF231338 mRNA Translation: AAF71306.1
AF231339 mRNA Translation: AAF71307.1
AF246960 mRNA Translation: AAL50339.1
AF246961 mRNA Translation: AAL50340.1
AF246962 mRNA Translation: AAL50341.1
AF246963 mRNA Translation: AAL50342.1
AK296706 mRNA Translation: BAH12415.1
AC068794 Genomic DNA No translation available.
AC092829 Genomic DNA No translation available.
BC000172 mRNA Translation: AAH00172.3
BC125061 mRNA Translation: AAI25062.1
BC125062 mRNA Translation: AAI25063.1
CCDSiCCDS58219.1 [Q8WYA1-2]
CCDS58220.1 [Q8WYA1-4]
CCDS58221.1 [Q8WYA1-3]
CCDS58222.1 [Q8WYA1-9]
CCDS8712.1 [Q8WYA1-1]
RefSeqiNP_001234931.1, NM_001248002.1 [Q8WYA1-2]
NP_001234932.1, NM_001248003.1 [Q8WYA1-3]
NP_001234933.1, NM_001248004.1 [Q8WYA1-4]
NP_001234934.1, NM_001248005.1 [Q8WYA1-9]
NP_064568.3, NM_020183.4 [Q8WYA1-1]
UniGeneiHs.445447

Genome annotation databases

EnsembliENST00000261178; ENSP00000261178; ENSG00000029153 [Q8WYA1-4]
ENST00000266503; ENSP00000266503; ENSG00000029153 [Q8WYA1-1]
ENST00000311001; ENSP00000312247; ENSG00000029153 [Q8WYA1-2]
ENST00000395901; ENSP00000379238; ENSG00000029153 [Q8WYA1-3]
ENST00000542388; ENSP00000445836; ENSG00000029153 [Q8WYA1-6]
ENST00000544915; ENSP00000442438; ENSG00000029153 [Q8WYA1-5]
ENST00000546179; ENSP00000438545; ENSG00000029153 [Q8WYA1-9]
GeneIDi56938
KEGGihsa:56938
UCSCiuc001rht.3 human [Q8WYA1-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiBMAL2_HUMAN
AccessioniPrimary (citable) accession number: Q8WYA1
Secondary accession number(s): B7Z429
, F5H402, Q8WYA2, Q8WYA3, Q8WYA4, Q96J63, Q9H2M4, Q9NS70, Q9NYQ4, Q9NYQ5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 23, 2007
Last sequence update: January 23, 2007
Last modified: July 18, 2018
This is version 146 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references

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