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O43918

- AIRE_HUMAN

UniProt

O43918 - AIRE_HUMAN

Protein

Autoimmune regulator

Gene

AIRE

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 158 (01 Oct 2014)
      Sequence version 1 (01 Jun 1998)
      Previous versions | rss
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    Functioni

    Transcriptional regulator that binds to DNA as a dimer or as a tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes By similarity. Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Functions as a transcriptional activator and promotes the expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance and the avoidance of autoimmune reactions.By similarity2 Publications

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri296 – 34348PHD-type 1PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri434 – 47542PHD-type 2PROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. chromatin binding Source: UniProtKB
    2. histone binding Source: UniProtKB
    3. protein binding Source: IntAct
    4. transcription regulatory region DNA binding Source: UniProtKB
    5. translation regulator activity Source: InterPro
    6. zinc ion binding Source: UniProtKB

    GO - Biological processi

    1. humoral immune response Source: Ensembl
    2. immune response Source: ProtInc
    3. positive regulation of transcription, DNA-templated Source: UniProtKB
    4. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    5. regulation of transcription, DNA-templated Source: UniProtKB
    6. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Autoimmune regulator
    Alternative name(s):
    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein
    Short name:
    APECED protein
    Gene namesi
    Name:AIRE
    Synonyms:APECED
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 21

    Organism-specific databases

    HGNCiHGNC:360. AIRE.

    Subcellular locationi

    Nucleus. Cytoplasm
    Note: Associated with tubular structures and in discrete nuclear dots resembling ND10 nuclear bodies. May shuttle between nucleus and cytoplasm.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Autoimmune polyendocrine syndrome 1, with or without reversible metaphyseal dysplasia (APS1) [MIM:240300]: A rare disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism.12 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry. Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes (PubMed:14974083).1 Publication
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti15 – 151R → C in APS1. 1 Publication
    Corresponds to variant rs179363875 [ dbSNP | Ensembl ].
    VAR_026480
    Natural varianti15 – 151R → L in APS1; prevents homooligomerization; slightly alters subcellular localization; no effect on the transcriptional transactivation activity. 1 Publication
    Corresponds to variant rs179363876 [ dbSNP | Ensembl ].
    VAR_013713
    Natural varianti16 – 161T → M in APS1; prevents homooligomerization; slightly alters subcellular localization; no effect on the transcriptional transactivation activity. 2 Publications
    Corresponds to variant rs179363877 [ dbSNP | Ensembl ].
    VAR_013714
    Natural varianti21 – 211A → V in APS1; no effect on homooligomerization; no effect on subcellular localization; no effect on the transcriptional transactivation activity. 1 Publication
    Corresponds to variant rs179363886 [ dbSNP | Ensembl ].
    VAR_026481
    Natural varianti22 – 232Missing in APS1; prevents homodimerization.
    VAR_026482
    Natural varianti28 – 281L → P in APS1; abolishes association with cytoplasmic tubular structures and homodimerization. 2 Publications
    Corresponds to variant rs179363878 [ dbSNP | Ensembl ].
    VAR_005004
    Natural varianti29 – 291L → P in APS1. 1 Publication
    Corresponds to variant rs179363879 [ dbSNP | Ensembl ].
    VAR_013715
    Natural varianti77 – 771F → S in APS1; loss of homooligomerization. 1 Publication
    Corresponds to variant rs179363887 [ dbSNP | Ensembl ].
    VAR_026483
    Natural varianti78 – 781W → R in APS1; loss of homooligomerization. 4 Publications
    Corresponds to variant rs179363880 [ dbSNP | Ensembl ].
    VAR_013716
    Natural varianti80 – 801V → L in APS1. 2 Publications
    Corresponds to variant rs179363881 [ dbSNP | Ensembl ].
    VAR_013717
    Natural varianti83 – 831K → E in APS1. 2 Publications
    VAR_005005
    Natural varianti85 – 851Y → C in APS1. 3 Publications
    Corresponds to variant rs179363882 [ dbSNP | Ensembl ].
    VAR_013718
    Natural varianti90 – 901Y → C in APS1. 1 Publication
    Corresponds to variant rs179363883 [ dbSNP | Ensembl ].
    VAR_013719
    Natural varianti93 – 931L → R in APS1. 1 Publication
    Corresponds to variant rs179363884 [ dbSNP | Ensembl ].
    VAR_013720
    Natural varianti228 – 2281G → W in APS1; changes the subcellular localization and in addition disrupts the transactivating capacity of the wild-type AIRE; acts with a dominant negative effect by binding to the wild-type AIRE thus preventing the protein from forming the complexes needed for transactivation. 1 Publication
    VAR_014422
    Natural varianti252 – 2521P → L in APS1. 1 Publication
    Corresponds to variant rs34397615 [ dbSNP | Ensembl ].
    VAR_026484
    Natural varianti301 – 3011V → M in APS1; no effect on protein structure or on interaction with histone H3. 1 Publication
    Corresponds to variant rs150634562 [ dbSNP | Ensembl ].
    VAR_013721
    Natural varianti311 – 3111C → Y in APS1; impairs zinc binding and folding of the PHD-type 1 zinc finger. 3 Publications
    VAR_013723
    Natural varianti326 – 3261P → L in APS1; no significant effect on structure, but may alter protein interactions. 1 Publication
    Corresponds to variant rs179363888 [ dbSNP | Ensembl ].
    VAR_026485
    Natural varianti326 – 3261P → Q in APS1; alters folding of the PHD-type 1 zinc finger. 2 Publications
    Corresponds to variant rs179363885 [ dbSNP | Ensembl ].
    VAR_013724
    Natural varianti539 – 5391P → L in APS1. 1 Publication
    Corresponds to variant rs179363889 [ dbSNP | Ensembl ].
    VAR_026486

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi295 – 2951N → A: Abolishes interaction with histone H3. 1 Publication
    Mutagenesisi297 – 2971D → A: Strongly reduces interaction with unmethylated histone H3 and abolishes interaction with histone H3 trimethylated at 'Lys-4'. 1 Publication
    Mutagenesisi298 – 2981E → A: Reduces interaction with histone H3. 1 Publication
    Mutagenesisi302 – 3021C → P: Reduces transcriptional activation. 1 Publication
    Mutagenesisi303 – 3031R → P: Alters protein folding and abolishes interaction with histone H3. 1 Publication
    Mutagenesisi304 – 3041D → A: Strongly reduces interaction with histone H3. 1 Publication
    Mutagenesisi307 – 3071E → A: Reduces interaction with histone H3. 1 Publication
    Mutagenesisi312 – 3121D → A: Abolishes interaction with histone H3. 1 Publication
    Mutagenesisi437 – 4371C → P: Reduces transcription activation. 1 Publication

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi109100. phenotype.
    240300. phenotype.
    Orphaneti3453. Autoimmune polyendocrinopathy type 1.
    PharmGKBiPA24654.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 545545Autoimmune regulatorPRO_0000064513Add
    BLAST

    Post-translational modificationi

    Phosphorylated. Phosphorylation could trigger oligomerization.1 Publication

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiO43918.
    PRIDEiO43918.

    PTM databases

    PhosphoSiteiO43918.

    Expressioni

    Tissue specificityi

    Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. Isoform 2 and isoform 3 seem to be less frequently expressed than isoform 1, if at all.

    Gene expression databases

    ArrayExpressiO43918.
    BgeeiO43918.
    CleanExiHS_AIRE.
    GenevestigatoriO43918.

    Organism-specific databases

    HPAiHPA038267.

    Interactioni

    Subunit structurei

    Homodimer and homotetramer. Interacts with CREBBP. Interacts preferentially with histone H3 that is not methylated at 'Lys-4'. Binds with lower affinity to histone H3 that is monomethylated at 'Lys-4'. Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3' abolish the interaction. Binds with lower affinity to histone H3 that is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at 'Arg-2' with very low affinity.5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    DAXXQ9UER75EBI-1753081,EBI-77321
    HIST1H3DP6843120EBI-1753081,EBI-79722
    NCK1P163332EBI-1753081,EBI-389883
    PRKDCP785272EBI-1753081,EBI-352053

    Protein-protein interaction databases

    BioGridi106823. 53 interactions.
    DIPiDIP-47504N.
    IntActiO43918. 23 interactions.
    MINTiMINT-6542056.
    STRINGi9606.ENSP00000291582.

    Structurei

    Secondary structure

    1
    545
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi298 – 3036
    Beta strandi306 – 3105
    Beta strandi312 – 3143
    Beta strandi317 – 3193
    Turni320 – 3223
    Beta strandi323 – 3253
    Helixi338 – 3425
    Turni423 – 4264
    Turni435 – 4373
    Beta strandi447 – 4493
    Helixi455 – 4584
    Turni460 – 4623
    Beta strandi467 – 4693
    Turni473 – 4764

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1XWHNMR-A293-354[»]
    2KE1NMR-A293-354[»]
    2KFTNMR-A294-347[»]
    2LRINMR-C423-485[»]
    ProteinModelPortaliO43918.
    SMRiO43918. Positions 294-347, 423-485.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO43918.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini1 – 105105HSRPROSITE-ProRule annotationAdd
    BLAST
    Domaini181 – 280100SANDPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni295 – 2984Interaction with histone H3 not methylated at 'Lys-4'
    Regioni304 – 3129Interaction with histone H3 not methylated at 'Lys-4'
    Regioni331 – 3355Interaction with histone H3 not methylated at 'Lys-4'

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi7 – 115LXXLL motif 1
    Motifi63 – 675LXXLL motif 2
    Motifi414 – 4185LXXLL motif 3
    Motifi516 – 5205LXXLL motif 4

    Domaini

    The L-X-X-L-L repeats may be implicated in binding to nuclear receptors.
    The HSR domain is required for localization on tubular structures (N-terminal part) and for homodimerization.
    Interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at 'Lys-4'. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function.

    Sequence similaritiesi

    Contains 1 HSR domain.PROSITE-ProRule annotation
    Contains 2 PHD-type zinc fingers.PROSITE-ProRule annotation
    Contains 1 SAND domain.PROSITE-ProRule annotation

    Zinc finger

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri296 – 34348PHD-type 1PROSITE-ProRule annotationAdd
    BLAST
    Zinc fingeri434 – 47542PHD-type 2PROSITE-ProRule annotationAdd
    BLAST

    Keywords - Domaini

    Repeat, Zinc-finger

    Phylogenomic databases

    eggNOGiNOG317492.
    HOGENOMiHOG000060093.
    HOVERGENiHBG014961.
    InParanoidiO43918.
    KOiK10603.
    OMAiAAILDFW.
    OrthoDBiEOG7ZSHT7.
    PhylomeDBiO43918.
    TreeFamiTF336193.

    Family and domain databases

    Gene3Di3.10.390.10. 1 hit.
    3.30.40.10. 2 hits.
    InterProiIPR008087. AIRE.
    IPR000770. SAND_dom.
    IPR010919. SAND_dom-like.
    IPR004865. Sp100.
    IPR019786. Zinc_finger_PHD-type_CS.
    IPR011011. Znf_FYVE_PHD.
    IPR001965. Znf_PHD.
    IPR019787. Znf_PHD-finger.
    IPR013083. Znf_RING/FYVE/PHD.
    [Graphical view]
    PfamiPF00628. PHD. 1 hit.
    PF01342. SAND. 1 hit.
    PF03172. Sp100. 1 hit.
    [Graphical view]
    PRINTSiPR01711. AIREGULATOR.
    SMARTiSM00249. PHD. 2 hits.
    SM00258. SAND. 1 hit.
    [Graphical view]
    SUPFAMiSSF57903. SSF57903. 2 hits.
    SSF63763. SSF63763. 1 hit.
    PROSITEiPS51414. HSR. 1 hit.
    PS50864. SAND. 1 hit.
    PS01359. ZF_PHD_1. 2 hits.
    PS50016. ZF_PHD_2. 1 hit.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Note: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

    Isoform 1 (identifier: O43918-1) [UniParc]FASTAAdd to Basket

    Also known as: AIRE-1

    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

    MATDAALRRL LRLHRTEIAV AVDSAFPLLH ALADHDVVPE DKFQETLHLK    50
    EKEGCPQAFH ALLSWLLTQD STAILDFWRV LFKDYNLERY GRLQPILDSF 100
    PKDVDLSQPR KGRKPPAVPK ALVPPPRLPT KRKASEEARA AAPAALTPRG 150
    TASPGSQLKA KPPKKPESSA EQQRLPLGNG IQTMSASVQR AVAMSSGDVP 200
    GARGAVEGIL IQQVFESGGS KKCIQVGGEF YTPSKFEDSG SGKNKARSSS 250
    GPKPLVRAKG AQGAAPGGGE ARLGQQGSVP APLALPSDPQ LHQKNEDECA 300
    VCRDGGELIC CDGCPRAFHL ACLSPPLREI PSGTWRCSSC LQATVQEVQP 350
    RAEEPRPQEP PVETPLPPGL RSAGEEVRGP PGEPLAGMDT TLVYKHLPAP 400
    PSAAPLPGLD SSALHPLLCV GPEGQQNLAP GARCGVCGDG TDVLRCTHCA 450
    AAFHWRCHFP AGTSRPGTGL RCRSCSGDVT PAPVEGVLAP SPARLAPGPA 500
    KDDTASHEPA LHRDDLESLL SEHTFDGILQ WAIQSMARPA APFPS 545
    Length:545
    Mass (Da):57,727
    Last modified:June 1, 1998 - v1
    Checksum:i8CF703F8C9411BC5
    GO
    Isoform 2 (identifier: O43918-2) [UniParc]FASTAAdd to Basket

    Also known as: AIRE-2

    The sequence of this isoform differs from the canonical sequence as follows:
         1-292: MATDAALRRL...LALPSDPQLH → MWLVYSSGAP...VALRRVLHPS

    Show »
    Length:338
    Mass (Da):35,507
    Checksum:i7C99ABAD92DDC565
    GO
    Isoform 3 (identifier: O43918-3) [UniParc]FASTAAdd to Basket

    Also known as: AIRE-3

    The sequence of this isoform differs from the canonical sequence as follows:
         1-292: MATDAALRRL...LALPSDPQLH → MWLVYSSGAP...VALRRVLHPS
         377-545: VRGPPGEPLA...MARPAAPFPS → PRCQGWTPRP...ACAADPAQET

    Show »
    Length:244
    Mass (Da):25,927
    Checksum:iBD26FC231E0E5611
    GO
    Isoform 4 (identifier: O43918-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-292: MATDAALRRL...LALPSDPQLH → MWLVYSSGAP...VALRRVLHPS
         293-293: Q → PVCMGVSCLCQ

    Note: No experimental confirmation available.

    Show »
    Length:348
    Mass (Da):36,501
    Checksum:i37045012FF585F6E
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti437 – 46731CGDGT…TSRPG → W in CAA08759. 1 PublicationCuratedAdd
    BLAST

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti15 – 151R → C in APS1. 1 Publication
    Corresponds to variant rs179363875 [ dbSNP | Ensembl ].
    VAR_026480
    Natural varianti15 – 151R → L in APS1; prevents homooligomerization; slightly alters subcellular localization; no effect on the transcriptional transactivation activity. 1 Publication
    Corresponds to variant rs179363876 [ dbSNP | Ensembl ].
    VAR_013713
    Natural varianti16 – 161T → M in APS1; prevents homooligomerization; slightly alters subcellular localization; no effect on the transcriptional transactivation activity. 2 Publications
    Corresponds to variant rs179363877 [ dbSNP | Ensembl ].
    VAR_013714
    Natural varianti21 – 211A → V in APS1; no effect on homooligomerization; no effect on subcellular localization; no effect on the transcriptional transactivation activity. 1 Publication
    Corresponds to variant rs179363886 [ dbSNP | Ensembl ].
    VAR_026481
    Natural varianti22 – 232Missing in APS1; prevents homodimerization.
    VAR_026482
    Natural varianti28 – 281L → P in APS1; abolishes association with cytoplasmic tubular structures and homodimerization. 2 Publications
    Corresponds to variant rs179363878 [ dbSNP | Ensembl ].
    VAR_005004
    Natural varianti29 – 291L → P in APS1. 1 Publication
    Corresponds to variant rs179363879 [ dbSNP | Ensembl ].
    VAR_013715
    Natural varianti77 – 771F → S in APS1; loss of homooligomerization. 1 Publication
    Corresponds to variant rs179363887 [ dbSNP | Ensembl ].
    VAR_026483
    Natural varianti78 – 781W → R in APS1; loss of homooligomerization. 4 Publications
    Corresponds to variant rs179363880 [ dbSNP | Ensembl ].
    VAR_013716
    Natural varianti80 – 801V → L in APS1. 2 Publications
    Corresponds to variant rs179363881 [ dbSNP | Ensembl ].
    VAR_013717
    Natural varianti83 – 831K → E in APS1. 2 Publications
    VAR_005005
    Natural varianti85 – 851Y → C in APS1. 3 Publications
    Corresponds to variant rs179363882 [ dbSNP | Ensembl ].
    VAR_013718
    Natural varianti90 – 901Y → C in APS1. 1 Publication
    Corresponds to variant rs179363883 [ dbSNP | Ensembl ].
    VAR_013719
    Natural varianti93 – 931L → R in APS1. 1 Publication
    Corresponds to variant rs179363884 [ dbSNP | Ensembl ].
    VAR_013720
    Natural varianti228 – 2281G → W in APS1; changes the subcellular localization and in addition disrupts the transactivating capacity of the wild-type AIRE; acts with a dominant negative effect by binding to the wild-type AIRE thus preventing the protein from forming the complexes needed for transactivation. 1 Publication
    VAR_014422
    Natural varianti252 – 2521P → L in APS1. 1 Publication
    Corresponds to variant rs34397615 [ dbSNP | Ensembl ].
    VAR_026484
    Natural varianti278 – 2781S → R.3 Publications
    Corresponds to variant rs1800520 [ dbSNP | Ensembl ].
    VAR_005006
    Natural varianti301 – 3011V → M in APS1; no effect on protein structure or on interaction with histone H3. 1 Publication
    Corresponds to variant rs150634562 [ dbSNP | Ensembl ].
    VAR_013721
    Natural varianti305 – 3051G → S.
    VAR_013722
    Natural varianti311 – 3111C → Y in APS1; impairs zinc binding and folding of the PHD-type 1 zinc finger. 3 Publications
    VAR_013723
    Natural varianti326 – 3261P → L in APS1; no significant effect on structure, but may alter protein interactions. 1 Publication
    Corresponds to variant rs179363888 [ dbSNP | Ensembl ].
    VAR_026485
    Natural varianti326 – 3261P → Q in APS1; alters folding of the PHD-type 1 zinc finger. 2 Publications
    Corresponds to variant rs179363885 [ dbSNP | Ensembl ].
    VAR_013724
    Natural varianti539 – 5391P → L in APS1. 1 Publication
    Corresponds to variant rs179363889 [ dbSNP | Ensembl ].
    VAR_026486

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 292292MATDA…DPQLH → MWLVYSSGAPGTQQPARNRV FFPIGMAPGGVCWRPDGWGT GGQGRISGPGSMGAGQRLGS SGTQRCCWGSCFGKEVALRR VLHPS in isoform 2, isoform 3 and isoform 4. 2 PublicationsVSP_004089Add
    BLAST
    Alternative sequencei293 – 2931Q → PVCMGVSCLCQ in isoform 4. 1 PublicationVSP_043529
    Alternative sequencei377 – 545169VRGPP…APFPS → PRCQGWTPRPCTPYCVWVLR VSRTWLLVRVAGCAEMVRTC CGVLTAPLPSTGAATSQPAP PGPGRACAADPAQET in isoform 3. 1 PublicationVSP_004090Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB006682 mRNA. Translation: BAA23988.1.
    AB006683 mRNA. Translation: BAA23989.1.
    AB006684 Genomic DNA. Translation: BAA23990.1.
    AB006684 Genomic DNA. Translation: BAA23991.1.
    AB006684 Genomic DNA. Translation: BAA23992.1.
    AB006685 mRNA. Translation: BAA23993.1.
    Z97990 mRNA. Translation: CAB10790.1.
    AJ009610 Genomic DNA. Translation: CAA08759.1.
    AP001754 Genomic DNA. Translation: BAA95560.1.
    AP001060 Genomic DNA. No translation available.
    CH471079 Genomic DNA. Translation: EAX09443.1.
    BC137268 mRNA. Translation: AAI37269.1.
    BC137270 mRNA. Translation: AAI37271.1.
    CCDSiCCDS13706.1. [O43918-1]
    RefSeqiNP_000374.1. NM_000383.3. [O43918-1]
    XP_005261167.1. XM_005261110.1. [O43918-4]
    UniGeneiHs.129829.

    Genome annotation databases

    EnsembliENST00000291582; ENSP00000291582; ENSG00000160224. [O43918-1]
    GeneIDi326.
    KEGGihsa:326.
    UCSCiuc002zei.3. human. [O43918-1]
    uc002zej.3. human. [O43918-4]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    AIREbase

    AIRE mutation db

    Mendelian genes autoimmune regulator (AIRE)

    Leiden Open Variation Database (LOVD)

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB006682 mRNA. Translation: BAA23988.1 .
    AB006683 mRNA. Translation: BAA23989.1 .
    AB006684 Genomic DNA. Translation: BAA23990.1 .
    AB006684 Genomic DNA. Translation: BAA23991.1 .
    AB006684 Genomic DNA. Translation: BAA23992.1 .
    AB006685 mRNA. Translation: BAA23993.1 .
    Z97990 mRNA. Translation: CAB10790.1 .
    AJ009610 Genomic DNA. Translation: CAA08759.1 .
    AP001754 Genomic DNA. Translation: BAA95560.1 .
    AP001060 Genomic DNA. No translation available.
    CH471079 Genomic DNA. Translation: EAX09443.1 .
    BC137268 mRNA. Translation: AAI37269.1 .
    BC137270 mRNA. Translation: AAI37271.1 .
    CCDSi CCDS13706.1. [O43918-1 ]
    RefSeqi NP_000374.1. NM_000383.3. [O43918-1 ]
    XP_005261167.1. XM_005261110.1. [O43918-4 ]
    UniGenei Hs.129829.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1XWH NMR - A 293-354 [» ]
    2KE1 NMR - A 293-354 [» ]
    2KFT NMR - A 294-347 [» ]
    2LRI NMR - C 423-485 [» ]
    ProteinModelPortali O43918.
    SMRi O43918. Positions 294-347, 423-485.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 106823. 53 interactions.
    DIPi DIP-47504N.
    IntActi O43918. 23 interactions.
    MINTi MINT-6542056.
    STRINGi 9606.ENSP00000291582.

    PTM databases

    PhosphoSitei O43918.

    Proteomic databases

    PaxDbi O43918.
    PRIDEi O43918.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000291582 ; ENSP00000291582 ; ENSG00000160224 . [O43918-1 ]
    GeneIDi 326.
    KEGGi hsa:326.
    UCSCi uc002zei.3. human. [O43918-1 ]
    uc002zej.3. human. [O43918-4 ]

    Organism-specific databases

    CTDi 326.
    GeneCardsi GC21P045705.
    HGNCi HGNC:360. AIRE.
    HPAi HPA038267.
    MIMi 109100. phenotype.
    240300. phenotype.
    607358. gene.
    neXtProti NX_O43918.
    Orphaneti 3453. Autoimmune polyendocrinopathy type 1.
    PharmGKBi PA24654.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG317492.
    HOGENOMi HOG000060093.
    HOVERGENi HBG014961.
    InParanoidi O43918.
    KOi K10603.
    OMAi AAILDFW.
    OrthoDBi EOG7ZSHT7.
    PhylomeDBi O43918.
    TreeFami TF336193.

    Miscellaneous databases

    EvolutionaryTracei O43918.
    GeneWikii Autoimmune_regulator.
    GenomeRNAii 326.
    NextBioi 1337.
    PROi O43918.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O43918.
    Bgeei O43918.
    CleanExi HS_AIRE.
    Genevestigatori O43918.

    Family and domain databases

    Gene3Di 3.10.390.10. 1 hit.
    3.30.40.10. 2 hits.
    InterProi IPR008087. AIRE.
    IPR000770. SAND_dom.
    IPR010919. SAND_dom-like.
    IPR004865. Sp100.
    IPR019786. Zinc_finger_PHD-type_CS.
    IPR011011. Znf_FYVE_PHD.
    IPR001965. Znf_PHD.
    IPR019787. Znf_PHD-finger.
    IPR013083. Znf_RING/FYVE/PHD.
    [Graphical view ]
    Pfami PF00628. PHD. 1 hit.
    PF01342. SAND. 1 hit.
    PF03172. Sp100. 1 hit.
    [Graphical view ]
    PRINTSi PR01711. AIREGULATOR.
    SMARTi SM00249. PHD. 2 hits.
    SM00258. SAND. 1 hit.
    [Graphical view ]
    SUPFAMi SSF57903. SSF57903. 2 hits.
    SSF63763. SSF63763. 1 hit.
    PROSITEi PS51414. HSR. 1 hit.
    PS50864. SAND. 1 hit.
    PS01359. ZF_PHD_1. 2 hits.
    PS50016. ZF_PHD_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3), VARIANT APS1 GLU-83.
      Tissue: Thymus.
    2. "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains."
      Aaltonen J., Bjoerses P., Perheentupa J., Horelli-Kuitunen N., Palotie A., Peltonen L., Lee Y.S., Francis F., Hennig S., Thiel C., Lehrach H., Yaspo M.-L.
      Nat. Genet. 17:399-403(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
      Tissue: Thymus.
    3. Lee Y.S., Francis F., Hennig S., Thiel C., Reinhard R., Lehrach H., Yaspo M.-L.
      Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "The DNA sequence of human chromosome 21."
      Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A.
      , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.
      Nature 405:311-319(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
    7. "Localization of the APECED protein in distinct nuclear structures."
      Bjoerses P., Pelto-Huikko M., Kaukonen J., Aaltonen J., Peltonen L., Ulmanen I.
      Hum. Mol. Genet. 8:259-266(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    8. Cited for: PARTIAL PROTEIN SEQUENCE, SUBUNIT STRUCTURE, DNA-BINDING, PHOSPHORYLATION.
    9. "Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein."
      Bjeorses P., Halonen M., Palvimo J.J., Kolmer M., Aaltonen J., Ellonen P., Perheentupa J., Ulmanen I., Peltonen L.
      Am. J. Hum. Genet. 66:378-392(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, VARIANTS APS1 LEU-80; CYS-85; TYR-311 AND GLN-326.
    10. "Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain."
      Pitkaenen J., Vaehaemurto P., Krohn K.J.E., Peterson P.
      J. Biol. Chem. 276:19597-19602(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF CYS-302 AND CYS-437, CHARACTERIZATION OF VARIANT APS1 PRO-28.
    11. "APECED-causing mutations in AIRE reveal the functional domains of the protein."
      Halonen M., Kangas H., Rueppell T., Ilmarinen T., Ollila J., Kolmer M., Vihinen M., Palvimo J., Saarela J., Ulmanen I., Eskelin P.
      Hum. Mutat. 23:245-257(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, CHARACTERIZATION OF VARIANTS APS1 LEU-15; MET-16; VAL-21; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83; CYS-90; ARG-93; TRP-228 AND GLN-326.
    12. "The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression."
      Org T., Chignola F., Hetenyi C., Gaetani M., Rebane A., Liiv I., Maran U., Mollica L., Bottomley M.J., Musco G., Peterson P.
      EMBO Rep. 9:370-376(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH HISTONE H3 NON-METHYLATED OR MONO-METHYLATED AT LYS-4, FUNCTION, MUTAGENESIS OF ASP-297 AND ASP-312, CHARACTERIZATION OF VARIANTS APS1 MET-301 AND TYR-311.
    13. "NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease."
      Bottomley M.J., Stier G., Pennacchini D., Legube G., Simon B., Akhtar A., Sattler M., Musco G.
      J. Biol. Chem. 280:11505-11512(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF VARIANTS APS1 MET-301; TYR-311 AND GLN-326.
    14. "The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation."
      Chignola F., Gaetani M., Rebane A., Org T., Mollica L., Zucchelli C., Spitaleri A., Mannella V., Peterson P., Musco G.
      Nucleic Acids Res. 37:2951-2961(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED HISTONE H3 N-TERMINUS, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF ASN-295; GLU-298; ARG-303; ASP-304 AND GLU-307, INTERACTION WITH HISTOME H3.
    15. "Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator."
      Chakravarty S., Zeng L., Zhou M.-M.
      Structure 17:670-679(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 294-347 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED HISTONE H3 N-TERMINUS, CHARACTERIZATION OF VARIANTS APS1 MET-301; TYR-311; LEU-326 AND GLN-326.
    16. Cited for: VARIANT APS1 PRO-28.
    17. Cited for: VARIANT ARG-278.
    18. "Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
      Saugier-Veber P., Drouot N., Wolf L.M., Kuhn J.M., Frebourg T., Lefebvre H.
      Eur. J. Endocrinol. 144:347-351(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT APS1 LEU-326.
    19. Cited for: VARIANTS APS1 LEU-15; MET-16; PRO-28; PR0-29; ARG-78; LEU-80; GLU-83; CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326, VARIANT ARG-278.
    20. "Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED."
      The MEWPE-APECED study group
      Cihakova D., Trebusak K., Heino M., Fadeyev V., Tiulpakov A., Battelino T., Tar A., Halasz Z., Bluemel P., Tawfik S., Krohn K., Lebl J., Peterson P.
      Hum. Mutat. 18:225-232(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS APS1 MET-16 AND ARG-78.
    21. "A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis."
      Cetani F., Barbesino G., Borsari S., Pardi E., Cianferotti L., Pinchera A., Marcocci C.
      J. Clin. Endocrinol. Metab. 86:4747-4752(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT APS1 TRP-228.
    22. "Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations."
      Kogawa K., Kudoh J., Nagafuchi S., Ohga S., Katsuta H., Ishibashi H., Harada M., Hara T., Shimizu N.
      Clin. Immunol. 103:277-283(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT APS1 PRO-29.
    23. "A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan."
      Sato K., Nakajima K., Imamura H., Deguchi T., Horinouchi S., Yamazaki K., Yamada E., Kanaji Y., Takano K.
      Endocr. J. 49:625-633(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT APS1 CYS-15, VARIANT ARG-278.
    24. "Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy."
      Meloni A., Perniola R., Faa V., Corvaglia E., Cao A., Rosatelli M.C.
      J. Clin. Endocrinol. Metab. 87:841-846(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS APS1 ARG-78; LEU-252 AND LEU-539.
    25. "AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype."
      Halonen M., Eskelin P., Myhre A.-G., Perheentupa J., Husebye E.S., Kaempe O., Rorsman F., Peltonen L., Ulmanen I., Partanen J.
      J. Clin. Endocrinol. Metab. 87:2568-2574(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS APS1 VAL-21; CYS-85 AND TYR-311.
    26. "Two novel mutations of the AIRE protein affecting its homodimerization properties."
      Meloni A., Fiorillo E., Corda D., Perniola R., Cao A., Rosatelli M.C.
      Hum. Mutat. 25:319-319(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS APS1 22-VAL-ASP-23 DEL; SER-77 AND ARG-78, CHARACTERIZATION OF VARIANTS APS1 LEU-15; MET-16; 22-VAL-ASP-23 DEL; SER-77 AND ARG-78.
    27. "Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation."
      Ilmarinen T., Eskelin P., Halonen M., Rueppell T., Kilpikari R., Torres G.D., Kangas H., Ulmanen I.
      Hum. Mutat. 26:322-331(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANT APS1 TRP-228.

    Entry informationi

    Entry nameiAIRE_HUMAN
    AccessioniPrimary (citable) accession number: O43918
    Secondary accession number(s): B2RP50
    , O43922, O43932, O75745
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1998
    Last sequence update: June 1, 1998
    Last modified: October 1, 2014
    This is version 158 of the entry and version 1 of the sequence. [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, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 21
      Human chromosome 21: 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
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3