Reviewed, UniProtKB/Swiss-Prot O43918 (AIRE_HUMAN)

Names and origin

Protein names

Autoimmune regulator
Also known as:
     Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein
     APECED protein

Gene names

Name:	AIRE
Synonyms:	APECED

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein existence

Evidence at protein level.

General annotation (Comments)

Function	Probable transcriptional regulator protein that binds to DNA as dimer and 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. May be involved in immune regulation.
Subunit structure	Homodimer and homotetramer. Interacts with CREBBP.
Subcellular location	Nucleus. Cytoplasm. Note=Associated with tubular structures and in discrete nuclear dots resembling ND10 nuclear bodies. May shuttle between nucleus and cytoplasm.
Tissue specificity	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. Isoforms 2 and 3 seem to be less frequently expressed than isoform 1, if at all.
Domain	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. 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.
Post-translational modification	Phosphorylated. Phosphorylation could trigger oligomerization.
Involvement in disease	Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APECED) [MIM:240300]; also known as autoimmune polyglandular syndrome type I (APS-1). APECED is an autosomal recessive disease characterized by: (1) autoimmune polyendocrinopathies: hypoparathyroidism, adrenocortical failure, IDDM, gonadal failure, hypothyroidism, pernicious anemia, and hepatitis; (2) chronic mucocutaneous candidiasis; (3) ectodermal dystrophies: vitiligo, alopecia, keratopathy, dystrophy of dental enamel, nails and tympanic membranes. In addition, a high proportion of patients develop squamous cell carcinoma of the oral mucosa. The disease is reported worldwide but is exceptionally prevalent among the Finnish population (incidence 1:25000) and the Iranian jews (incidence 1:9000). 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.
Sequence similarities	Contains 1 HSR domain. Contains 2 PHD-type zinc fingers. Contains 1 SAND domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	Immune response Ref.2 Traceable author statement. Source: ProtInc Regulation of transcription, DNA-dependent Ref.2 Non-traceable author statement. Source: UniProtKB
Cellular component	Nucleus Ref.1 Ref.2 Non-traceable author statement. Source: UniProtKB
Molecular function	Transcription factor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. Notes: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms. [Align] [Select]

Isoform 1 (identifier: O43918-1)
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.

Isoform 2 (identifier: O43918-2)
Also known as AIRE-2;
The sequence of this isoform differs from the canonical sequence as follows:
     1-292 MATDAALRRL...LALPSDPQLH → MWLVYSSGAP...VALRRVLHPS

Isoform 3 (identifier: O43918-3)
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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 545

545

Autoimmune regulator

Regions

Domain

1 – 106

106

HSR

Domain

181 – 280

100

SAND

Zinc finger

296 – 343

48

PHD-type 1

Zinc finger

434 – 475

42

PHD-type 2

Motif

7 – 11

5

LXXLL motif 1

Motif

63 – 67

5

LXXLL motif 2

Motif

414 – 418

5

LXXLL motif 3

Motif

516 – 520

5

LXXLL motif 4

Natural variations

Alternative sequence

1 – 292

292

MATDA…DPQLH → MWLVYSSGAPGTQQPARNRV FFPIGMAPGGVCWRPDGWGT GGQGRISGPGSMGAGQRLGS SGTQRCCWGSCFGKEVALRR VLHPS in isoform 2 and isoform 3.

Alternative sequence

377 – 545

169

VRGPP…APFPS → PRCQGWTPRPCTPYCVWVLR VSRTWLLVRVAGCAEMVRTC CGVLTAPLPSTGAATSQPAP PGPGRACAADPAQET in isoform 3.

Natural variant

15

1

R → C in APECED.

Natural variant

15

1

R → L in APECED; enzymatic activity of approximately 30% of that of the wild-type.

Natural variant

16

1

T → M in APECED; enzymatic activity of approximately 10% of that of the wild-type.

Natural variant

21

1

A → V in APECED.

Natural variant

22 – 23

2

Missing in APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization.

Natural variant

28

1

L → P in APECED; abolishes association with cytoplasmic tubular structures and homodimerization.

Natural variant

29

1

L → P in APECED.

Natural variant

77

1

F → S in APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization.

Natural variant

78

1

W → R in APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization.

Natural variant

80

1

V → L in APECED.

Natural variant

83

1

K → E in APECED.

Natural variant

85

1

Y → C in APECED.

Natural variant

90

1

Y → C in APECED.

Natural variant

93

1

L → R in APECED.

Natural variant

228

1

G → W in APECED; 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.

Natural variant

252

1

P → L in APECED.

Natural variant

278

1

S → R: dbSNP rs1800520.

Natural variant

301

1

V → M in APECED; no effect on protein structure.

Natural variant

305

1

G → S

Natural variant

311

1

C → Y in APECED; impairs zinc binding and folding of the PHD-type 1 zinc finger.

Natural variant

326

1

P → L in APECED.

Natural variant

326

1

P → Q in APECED; alters folding of the PHD-type 1 zinc finger.

Natural variant

539

1

P → L in APECED.

Experimental info

Mutagenesis

302

1

C → P: Reduces transcription activation

Mutagenesis

437

1

C → P: Reduces transcription activation

Sequence conflict

437 – 467

31

CGDGT…TSRPG → W in CAA08759. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

545

Helix Strand Turn

Details...

Beta strand

298 – 303

6

Turn

320 – 322

3

Beta strand

323 – 325

3

Helix

338 – 342

5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (AIRE-1) [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 8CF703F8C9411BC5	FASTA	545	57,727
	10 20 30 40 50 60 MATDAALRRL LRLHRTEIAV AVDSAFPLLH ALADHDVVPE DKFQETLHLK EKEGCPQAFH 70 80 90 100 110 120 ALLSWLLTQD STAILDFWRV LFKDYNLERY GRLQPILDSF PKDVDLSQPR KGRKPPAVPK 130 140 150 160 170 180 ALVPPPRLPT KRKASEEARA AAPAALTPRG TASPGSQLKA KPPKKPESSA EQQRLPLGNG 190 200 210 220 230 240 IQTMSASVQR AVAMSSGDVP GARGAVEGIL IQQVFESGGS KKCIQVGGEF YTPSKFEDSG 250 260 270 280 290 300 SGKNKARSSS GPKPLVRAKG AQGAAPGGGE ARLGQQGSVP APLALPSDPQ LHQKNEDECA 310 320 330 340 350 360 VCRDGGELIC CDGCPRAFHL ACLSPPLREI PSGTWRCSSC LQATVQEVQP RAEEPRPQEP 370 380 390 400 410 420 PVETPLPPGL RSAGEEVRGP PGEPLAGMDT TLVYKHLPAP PSAAPLPGLD SSALHPLLCV 430 440 450 460 470 480 GPEGQQNLAP GARCGVCGDG TDVLRCTHCA AAFHWRCHFP AGTSRPGTGL RCRSCSGDVT 490 500 510 520 530 540 PAPVEGVLAP SPARLAPGPA KDDTASHEPA LHRDDLESLL SEHTFDGILQ WAIQSMARPA APFPS
	Isoform 2 (AIRE-2) [UniParc]. Checksum: 7C99ABAD92DDC565		338	35,507
	10 20 30 40 50 60 MWLVYSSGAP GTQQPARNRV FFPIGMAPGG VCWRPDGWGT GGQGRISGPG SMGAGQRLGS 70 80 90 100 110 120 SGTQRCCWGS CFGKEVALRR VLHPSQKNED ECAVCRDGGE LICCDGCPRA FHLACLSPPL 130 140 150 160 170 180 REIPSGTWRC SSCLQATVQE VQPRAEEPRP QEPPVETPLP PGLRSAGEEV RGPPGEPLAG 190 200 210 220 230 240 MDTTLVYKHL PAPPSAAPLP GLDSSALHPL LCVGPEGQQN LAPGARCGVC GDGTDVLRCT 250 260 270 280 290 300 HCAAAFHWRC HFPAGTSRPG TGLRCRSCSG DVTPAPVEGV LAPSPARLAP GPAKDDTASH 310 320 330 EPALHRDDLE SLLSEHTFDG ILQWAIQSMA RPAAPFPS
	Isoform 3 (AIRE-3) [UniParc]. Checksum: BD26FC231E0E5611		244	25,927
	10 20 30 40 50 60 MWLVYSSGAP GTQQPARNRV FFPIGMAPGG VCWRPDGWGT GGQGRISGPG SMGAGQRLGS 70 80 90 100 110 120 SGTQRCCWGS CFGKEVALRR VLHPSQKNED ECAVCRDGGE LICCDGCPRA FHLACLSPPL 130 140 150 160 170 180 REIPSGTWRC SSCLQATVQE VQPRAEEPRP QEPPVETPLP PGLRSAGEEP RCQGWTPRPC 190 200 210 220 230 240 TPYCVWVLRV SRTWLLVRVA GCAEMVRTCC GVLTAPLPST GAATSQPAPP GPGRACAADP AQET

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Positional cloning of the APECED gene." Nagamine K., Peterson P., Scott H.S., Kudoh J., Minoshima S., Heino M., Krohn K.J.E., Lalioti M.D., Mullis P.E., Antonarakis S.E., Kawasaki K., Asakawa S., Ito F., Shimizu N. Nat. Genet. 17:393-398(1997) [PubMed: 9398839] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3), VARIANT APECED 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: 9398840] [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: 10830953] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: 9931333] [Abstract] Cited for: SUBCELLULAR LOCATION.
[6]	"The autoimmune regulator (AIRE) is a DNA-binding protein." Kumar P.G., Laloraya M., Wang C.-Y., Ruan Q.-G., Davoodi-Semiromi A., Kao K.-J., She J.-X. J. Biol. Chem. 276:41357-41364(2001) [PubMed: 11533054] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, SUBUNIT STRUCTURE, DNA-BINDING, PHOSPHORYLATION.
[7]	"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: 10677297] [Abstract] Cited for: SUBCELLULAR LOCATION, VARIANTS APECED LEU-80; CYS-85; TYR-311 AND GLN-326.
[8]	"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: 11274163] [Abstract] Cited for: SUBCELLULAR LOCATION, TRANSCRIPTION ACTIVATION, MUTAGENESIS OF CYS-302 AND CYS-437, CHARACTERIZATION OF VARIANT APECED PRO-28.
[9]	"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: 14974083] [Abstract] Cited for: SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS APECED 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.
[10]	"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: 15649886] [Abstract] Cited for: STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF APECED VARIANTS MET-301; TYR-311 AND GLN-326.
[11]	"Mutation analyses of North American APS-1 patients." Heino M., Scott H.S., Chen Q., Peterson P., Maeenpaeae U., Papasavvas M.-P., Mittaz L., Barras C., Rossier C., Chrousos G.P., Stratakis C.A., Nagamine K., Kudoh J., Shimizu N., Maclaren N., Antonarakis S.E., Krohn K.J.E. Hum. Mutat. 13:69-74(1999) [PubMed: 9888391] [Abstract] Cited for: VARIANT APECED PRO-28.
[12]	"Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins." Scott H.S., Heino M., Peterson P., Mittaz L., Lalioti M.D., Betterle C., Cohen A., Seri M., Lerone M., Romeo G., Collin P., Salo M., Metcalfe R., Weetman A., Papasavvas M.-P., Rossier C., Nagamine K., Kudoh J. , Shimizu N., Krohn K.J.E., Antonarakis S.E. Mol. Endocrinol. 12:1112-1119(1998) [PubMed: 9717837] [Abstract] Cited for: VARIANT ARG-278.
[13]	"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: 11275943] [Abstract] Cited for: VARIANT APECED LEU-326.
[14]	"APECED mutations in the autoimmune regulator (AIRE) gene." Heino M., Peterson P., Kudoh J., Shimizu N., Antonarakis S.E., Scott H.S., Krohn K.J.E. Hum. Mutat. 18:205-211(2001) [PubMed: 11524731] [Abstract] Cited for: VARIANTS APECED 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.
[15]	"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: 11524733] [Abstract] Cited for: VARIANTS APECED MET-16 AND ARG-78.
[16]	"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: 11600535] [Abstract] Cited for: VARIANT APECED TRP-228.
[17]	"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: 12173302] [Abstract] Cited for: VARIANT APECED PRO-29.
[18]	"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: 12625412] [Abstract] Cited for: VARIANT APECED CYS-15.
[19]	"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: 11836330] [Abstract] Cited for: VARIANTS APECED ARG-78; LEU-252 AND LEU-539.
[20]	"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: 12050215] [Abstract] Cited for: VARIANTS APECED VAL-21; CYS-85 AND TYR-311.
[21]	"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: 15712268] [Abstract] Cited for: VARIANTS APECED 22-VAL-ASP-23 DEL; SER-77 AND ARG-78, CHARACTERIZATION OF VARIANTS APECED LEU-15; MET-16; 22-VAL-ASP-23 DEL; SER-77 AND ARG-78.
[22]	"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: 16114041] [Abstract] Cited for: CHARACTERIZATION OF VARIANT APECED TRP-228.

Web resources

AIREbase

AIRE mutation db

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	AB006682 mRNA. Translation: BAA23988.1. AB006683 mRNA. Translation: BAA23989.1.