AIRE_HUMAN
ID AIRE_HUMAN Reviewed; 545 AA.
AC O43918; B2RP50; O43922; O43932; O75745;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 219.
DE RecName: Full=Autoimmune regulator;
DE AltName: Full=Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein;
DE Short=APECED protein;
GN Name=AIRE; Synonyms=APECED;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3), AND VARIANT
RP APS1 GLU-83.
RC TISSUE=Thymus;
RX PubMed=9398839; DOI=10.1038/ng1297-393;
RA Nagamine K., Peterson P., Scott H.S., Kudoh J., Minoshima S., Heino M.,
RA Krohn K.J.E., Lalioti M.D., Mullis P.E., Antonarakis S.E., Kawasaki K.,
RA Asakawa S., Ito F., Shimizu N.;
RT "Positional cloning of the APECED gene.";
RL Nat. Genet. 17:393-398(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC TISSUE=Thymus;
RX PubMed=9398840; DOI=10.1038/ng1297-399;
RA Aaltonen J., Bjoerses P., Perheentupa J., Horelli-Kuitunen N., Palotie A.,
RA Peltonen L., Lee Y.S., Francis F., Hennig S., Thiel C., Lehrach H.,
RA Yaspo M.-L.;
RT "An autoimmune disease, APECED, caused by mutations in a novel gene
RT featuring two PHD-type zinc-finger domains.";
RL Nat. Genet. 17:399-403(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Lee Y.S., Francis F., Hennig S., Thiel C., Reinhard R., Lehrach H.,
RA Yaspo M.-L.;
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=9931333; DOI=10.1093/hmg/8.2.259;
RA Bjoerses P., Pelto-Huikko M., Kaukonen J., Aaltonen J., Peltonen L.,
RA Ulmanen I.;
RT "Localization of the APECED protein in distinct nuclear structures.";
RL Hum. Mol. Genet. 8:259-266(1999).
RN [8]
RP PARTIAL PROTEIN SEQUENCE, SUBUNIT STRUCTURE, DNA-BINDING, AND
RP PHOSPHORYLATION.
RX PubMed=11533054; DOI=10.1074/jbc.m104898200;
RA Kumar P.G., Laloraya M., Wang C.-Y., Ruan Q.-G., Davoodi-Semiromi A.,
RA Kao K.-J., She J.-X.;
RT "The autoimmune regulator (AIRE) is a DNA-binding protein.";
RL J. Biol. Chem. 276:41357-41364(2001).
RN [9]
RP SUBCELLULAR LOCATION, AND VARIANTS APS1 LEU-80; CYS-85; TYR-311 AND
RP GLN-326.
RX PubMed=10677297; DOI=10.1086/302765;
RA Bjeorses P., Halonen M., Palvimo J.J., Kolmer M., Aaltonen J., Ellonen P.,
RA Perheentupa J., Ulmanen I., Peltonen L.;
RT "Mutations in the AIRE gene: effects on subcellular location and
RT transactivation function of the autoimmune polyendocrinopathy-candidiasis-
RT ectodermal dystrophy protein.";
RL Am. J. Hum. Genet. 66:378-392(2000).
RN [10]
RP SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF CYS-302 AND CYS-437, AND
RP CHARACTERIZATION OF VARIANT APS1 PRO-28.
RX PubMed=11274163; DOI=10.1074/jbc.m008322200;
RA Pitkaenen J., Vaehaemurto P., Krohn K.J.E., Peterson P.;
RT "Subcellular localization of the autoimmune regulator protein.
RT characterization of nuclear targeting and transcriptional activation
RT domain.";
RL J. Biol. Chem. 276:19597-19602(2001).
RN [11]
RP SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, AND CHARACTERIZATION OF VARIANTS
RP APS1 LEU-15; MET-16; VAL-21; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83;
RP CYS-90; ARG-93; TRP-228 AND GLN-326.
RX PubMed=14974083; DOI=10.1002/humu.20003;
RA Halonen M., Kangas H., Rueppell T., Ilmarinen T., Ollila J., Kolmer M.,
RA Vihinen M., Palvimo J., Saarela J., Ulmanen I., Eskelin P.;
RT "APECED-causing mutations in AIRE reveal the functional domains of the
RT protein.";
RL Hum. Mutat. 23:245-257(2004).
RN [12]
RP INTERACTION WITH HISTONE H3 NON-METHYLATED OR MONO-METHYLATED AT LYS-4,
RP FUNCTION, MUTAGENESIS OF ASP-297 AND ASP-312, AND CHARACTERIZATION OF
RP VARIANTS APS1 MET-301 AND TYR-311.
RX PubMed=18292755; DOI=10.1038/sj.embor.2008.11;
RA Org T., Chignola F., Hetenyi C., Gaetani M., Rebane A., Liiv I., Maran U.,
RA Mollica L., Bottomley M.J., Musco G., Peterson P.;
RT "The autoimmune regulator PHD finger binds to non-methylated histone H3K4
RT to activate gene expression.";
RL EMBO Rep. 9:370-376(2008).
RN [13]
RP REVIEW OF FUNCTION IN SELF-TOLERANCE.
RX PubMed=19302042; DOI=10.1146/annurev.immunol.25.022106.141532;
RA Mathis D., Benoist C.;
RT "Aire.";
RL Annu. Rev. Immunol. 27:287-312(2009).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=23993652; DOI=10.1016/j.immuni.2013.08.005;
RA Gardner J.M., Metzger T.C., McMahon E.J., Au-Yeung B.B., Krawisz A.K.,
RA Lu W., Price J.D., Johannes K.P., Satpathy A.T., Murphy K.M., Tarbell K.V.,
RA Weiss A., Anderson M.S.;
RT "Extrathymic Aire-expressing cells are a distinct bone marrow-derived
RT population that induce functional inactivation of CD4[?] T cells.";
RL Immunity 39:560-572(2013).
RN [15]
RP REVIEW OF FUNCTION IN SELF-TOLERANCE.
RX PubMed=26972725; DOI=10.1038/nri.2016.9;
RA Anderson M.S., Su M.A.;
RT "AIRE expands: new roles in immune tolerance and beyond.";
RL Nat. Rev. Immunol. 16:247-258(2016).
RN [16]
RP STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS, AND CHARACTERIZATION
RP OF VARIANTS APS1 MET-301; TYR-311 AND GLN-326.
RX PubMed=15649886; DOI=10.1074/jbc.m413959200;
RA Bottomley M.J., Stier G., Pennacchini D., Legube G., Simon B., Akhtar A.,
RA Sattler M., Musco G.;
RT "NMR structure of the first PHD finger of autoimmune regulator protein
RT (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal
RT dystrophy (APECED) disease.";
RL J. Biol. Chem. 280:11505-11512(2005).
RN [17]
RP STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED
RP HISTONE H3 N-TERMINUS, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF
RP ASN-295; GLU-298; ARG-303; ASP-304 AND GLU-307, AND INTERACTION WITH
RP HISTOME H3.
RX PubMed=19293276; DOI=10.1093/nar/gkp166;
RA Chignola F., Gaetani M., Rebane A., Org T., Mollica L., Zucchelli C.,
RA Spitaleri A., Mannella V., Peterson P., Musco G.;
RT "The solution structure of the first PHD finger of autoimmune regulator in
RT complex with non-modified histone H3 tail reveals the antagonistic role of
RT H3R2 methylation.";
RL Nucleic Acids Res. 37:2951-2961(2009).
RN [18]
RP STRUCTURE BY NMR OF 294-347 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED
RP HISTONE H3 N-TERMINUS, AND CHARACTERIZATION OF VARIANTS APS1 MET-301;
RP TYR-311; LEU-326 AND GLN-326.
RX PubMed=19446523; DOI=10.1016/j.str.2009.02.017;
RA Chakravarty S., Zeng L., Zhou M.-M.;
RT "Structure and site-specific recognition of histone H3 by the PHD finger of
RT human autoimmune regulator.";
RL Structure 17:670-679(2009).
RN [19]
RP VARIANT APS1 PRO-28.
RX PubMed=9888391;
RX DOI=10.1002/(sici)1098-1004(1999)13:1<69::aid-humu8>3.0.co;2-6;
RA Heino M., Scott H.S., Chen Q., Peterson P., Maeenpaeae U.,
RA Papasavvas M.-P., Mittaz L., Barras C., Rossier C., Chrousos G.P.,
RA Stratakis C.A., Nagamine K., Kudoh J., Shimizu N., Maclaren N.,
RA Antonarakis S.E., Krohn K.J.E.;
RT "Mutation analyses of North American APS-1 patients.";
RL Hum. Mutat. 13:69-74(1999).
RN [20]
RP VARIANT ARG-278.
RX PubMed=9717837; DOI=10.1210/mend.12.8.0143;
RA Scott H.S., Heino M., Peterson P., Mittaz L., Lalioti M.D., Betterle C.,
RA Cohen A., Seri M., Lerone M., Romeo G., Collin P., Salo M., Metcalfe R.,
RA Weetman A., Papasavvas M.-P., Rossier C., Nagamine K., Kudoh J.,
RA Shimizu N., Krohn K.J.E., Antonarakis S.E.;
RT "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal
RT dystrophy patients of different origins.";
RL Mol. Endocrinol. 12:1112-1119(1998).
RN [21]
RP VARIANT APS1 LEU-326.
RX PubMed=11275943; DOI=10.1530/eje.0.1440347;
RA Saugier-Veber P., Drouot N., Wolf L.M., Kuhn J.M., Frebourg T.,
RA Lefebvre H.;
RT "Identification of a novel mutation in the autoimmune regulator (AIRE-1)
RT gene in a French family with autoimmune polyendocrinopathy-candidiasis-
RT ectodermal dystrophy.";
RL Eur. J. Endocrinol. 144:347-351(2001).
RN [22]
RP VARIANTS APS1 LEU-15; MET-16; PRO-28; PR0-29; ARG-78; LEU-80; GLU-83;
RP CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326, AND VARIANT ARG-278.
RX PubMed=11524731; DOI=10.1002/humu.1176;
RA Heino M., Peterson P., Kudoh J., Shimizu N., Antonarakis S.E., Scott H.S.,
RA Krohn K.J.E.;
RT "APECED mutations in the autoimmune regulator (AIRE) gene.";
RL Hum. Mutat. 18:205-211(2001).
RN [23]
RP VARIANTS APS1 MET-16 AND ARG-78.
RX PubMed=11524733; DOI=10.1002/humu.1178;
RG The MEWPE-APECED study group;
RA Cihakova D., Trebusak K., Heino M., Fadeyev V., Tiulpakov A., Battelino T.,
RA Tar A., Halasz Z., Bluemel P., Tawfik S., Krohn K., Lebl J., Peterson P.;
RT "Novel AIRE mutations and P450 cytochrome autoantibodies in Central and
RT Eastern European patients with APECED.";
RL Hum. Mutat. 18:225-232(2001).
RN [24]
RP VARIANT APS1 TRP-228.
RX PubMed=11600535; DOI=10.1210/jcem.86.10.7884;
RA Cetani F., Barbesino G., Borsari S., Pardi E., Cianferotti L., Pinchera A.,
RA Marcocci C.;
RT "A novel mutation of the autoimmune regulator gene in an Italian kindred
RT with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting
RT in a dominant fashion and strongly cosegregating with hypothyroid
RT autoimmune thyroiditis.";
RL J. Clin. Endocrinol. Metab. 86:4747-4752(2001).
RN [25]
RP VARIANT APS1 PRO-29.
RX PubMed=12173302; DOI=10.1006/clim.2002.5208;
RA Kogawa K., Kudoh J., Nagafuchi S., Ohga S., Katsuta H., Ishibashi H.,
RA Harada M., Hara T., Shimizu N.;
RT "Distinct clinical phenotype and immunoreactivity in Japanese siblings with
RT autoimmune polyglandular syndrome type 1 (APS-1) associated with compound
RT heterozygous novel AIRE gene mutations.";
RL Clin. Immunol. 103:277-283(2002).
RN [26]
RP VARIANT APS1 CYS-15, AND VARIANT ARG-278.
RX PubMed=12625412; DOI=10.1507/endocrj.49.625;
RA Sato K., Nakajima K., Imamura H., Deguchi T., Horinouchi S., Yamazaki K.,
RA Yamada E., Kanaji Y., Takano K.;
RT "A novel missense mutation of AIRE gene in a patient with autoimmune
RT polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED),
RT accompanied with progressive muscular atrophy: case report and review of
RT the literature in Japan.";
RL Endocr. J. 49:625-633(2002).
RN [27]
RP VARIANTS APS1 ARG-78; LEU-252 AND LEU-539.
RX PubMed=11836330; DOI=10.1210/jcem.87.2.8209;
RA Meloni A., Perniola R., Faa V., Corvaglia E., Cao A., Rosatelli M.C.;
RT "Delineation of the molecular defects in the AIRE gene in autoimmune
RT polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern
RT Italy.";
RL J. Clin. Endocrinol. Metab. 87:841-846(2002).
RN [28]
RP VARIANTS APS1 VAL-21; CYS-85 AND TYR-311.
RX PubMed=12050215; DOI=10.1210/jcem.87.6.8564;
RA Halonen M., Eskelin P., Myhre A.-G., Perheentupa J., Husebye E.S.,
RA Kaempe O., Rorsman F., Peltonen L., Ulmanen I., Partanen J.;
RT "AIRE mutations and human leukocyte antigen genotypes as determinants of
RT the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
RT phenotype.";
RL J. Clin. Endocrinol. Metab. 87:2568-2574(2002).
RN [29]
RP VARIANTS APS1 22-VAL-ASP-23 DEL; SER-77 AND ARG-78, AND CHARACTERIZATION OF
RP VARIANTS APS1 LEU-15; MET-16; 22-VAL-ASP-23 DEL; SER-77 AND ARG-78.
RX PubMed=15712268; DOI=10.1002/humu.9309;
RA Meloni A., Fiorillo E., Corda D., Perniola R., Cao A., Rosatelli M.C.;
RT "Two novel mutations of the AIRE protein affecting its homodimerization
RT properties.";
RL Hum. Mutat. 25:319-319(2005).
RN [30]
RP CHARACTERIZATION OF VARIANTS APS1 PRO-28; CYS-85; TRP-228 AND LEU-252.
RX PubMed=16114041; DOI=10.1002/humu.20224;
RA Ilmarinen T., Eskelin P., Halonen M., Rueppell T., Kilpikari R.,
RA Torres G.D., Kangas H., Ulmanen I.;
RT "Functional analysis of SAND mutations in AIRE supports dominant
RT inheritance of the G228W mutation.";
RL Hum. Mutat. 26:322-331(2005).
RN [31]
RP INVOLVEMENT IN APS1, FUNCTION, SUBCELLULAR LOCATION, VARIANTS APS1 PRO-28;
RP CYS-90; MET-301; TYR-311 AND LEU-326, CHARACTERIZATION OF VARIANTS PRO-28;
RP CYS-90; MET-301; TYR-311 AND LEU-326, MUTAGENESIS OF 28-LEU-LEU-29; LEU-97;
RP ASP-297; ARG-303; ASP-312; CYS-446 AND ARG-471, VARIANTS LYS-298; TRP-299;
RP TYR-302; GLN-303; TRP-303; SER-305; ARG-306; MET-309; GLN-316; TRP-316;
RP PRO-319; GLN-328; TRP-328; ARG-332 AND ALA-484, AND CHARACTERIZATION OF
RP VARIANTS LYS-298; TYR-302; SER-305 AND GLN-328.
RX PubMed=26084028; DOI=10.1016/j.immuni.2015.04.021;
RA Oftedal B.E., Hellesen A., Erichsen M.M., Bratland E., Vardi A.,
RA Perheentupa J., Kemp E.H., Fiskerstrand T., Viken M.K., Weetman A.P.,
RA Fleishman S.J., Banka S., Newman W.G., Sewell W.A., Sozaeva L.S.,
RA Zayats T., Haugarvoll K., Orlova E.M., Haavik J., Johansson S.,
RA Knappskog P.M., Loevaas K., Wolff A.S., Abramson J., Husebye E.S.;
RT "Dominant mutations in the autoimmune regulator AIRE are associated with
RT common organ-specific autoimmune diseases.";
RL Immunity 42:1185-1196(2015).
RN [32]
RP INVOLVEMENT IN APS1, AND FUNCTION.
RX PubMed=27426947; DOI=10.1016/j.cell.2016.06.024;
RG APECED patient collaborative;
RA Meyer S., Woodward M., Hertel C., Vlaicu P., Haque Y., Kaerner J.,
RA Macagno A., Onuoha S.C., Fishman D., Peterson H., Metskuela K., Uibo R.,
RA Jaentti K., Hokynar K., Wolff A.S., Krohn K., Ranki A., Peterson P.,
RA Kisand K., Hayday A.;
RT "AIRE-deficient patients harbor unique high-affinity disease-ameliorating
RT autoantibodies.";
RL Cell 166:582-595(2016).
CC -!- FUNCTION: Transcription factor playing an essential role to promote
CC self-tolerance in the thymus by regulating the expression of a wide
CC array of self-antigens that have the commonality of being tissue-
CC restricted in their expression pattern in the periphery, called tissue
CC restricted antigens (TRA) (PubMed:26084028). Binds to G-doublets in an
CC A/T-rich environment; the preferred motif is a tandem repeat of 5'-
CC ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By
CC similarity). Binds to chromatin and interacts selectively with histone
CC H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and
CC not methylated at 'Arg-2'. Functions as a sensor of histone H3
CC modifications that are important for the epigenetic regulation of gene
CC expression. Mainly expressed by medullary thymic epithelial cells
CC (mTECs), induces the expression of thousands of tissue-restricted
CC proteins, which are presented on major histocompatibility complex class
CC I (MHC-I) and MHC-II molecules to developing T-cells percolating
CC through the thymic medulla (PubMed:26084028). Also induces self-
CC tolerance through other mechanisms such as the regulation of the mTEC
CC differentiation program. Controls the medullary accumulation of thymic
CC dendritic cells and the development of regulatory T-cell through the
CC regulation of XCL1 expression. Regulates the production of CCR4 and
CC CCR7 ligands in medullary thymic epithelial cells and alters the
CC coordinated maturation and migration of thymocytes. In thimic B-cells,
CC allows the presentation of licensing-dependent endogenous self-anitgen
CC for negative selection. In secondary lymphoid organs, induces
CC functional inactivation of CD4(+) T-cells. Expressed by a distinct bone
CC marrow-derived population, induces self-tolerance through a mechanism
CC that does not require regulatory T-cells and is resitant to innate
CC inflammatory stimuli (By similarity). {ECO:0000250|UniProtKB:Q9Z0E3,
CC ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:18292755,
CC ECO:0000269|PubMed:26084028, ECO:0000305|PubMed:19302042,
CC ECO:0000305|PubMed:26972725}.
CC -!- SUBUNIT: Homodimer and homotetramer. Interacts with CREBBP. Interacts
CC preferentially with histone H3 that is not methylated at 'Lys-4'. Binds
CC with lower affinity to histone H3 that is monomethylated at 'Lys-4'.
CC Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3'
CC abolish the interaction. Binds with lower affinity to histone H3 that
CC is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or
CC trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at
CC 'Arg-2' with very low affinity. {ECO:0000269|PubMed:11533054,
CC ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755,
CC ECO:0000269|PubMed:19293276, ECO:0000269|PubMed:19446523}.
CC -!- INTERACTION:
CC O43918; O43918: AIRE; NbExp=3; IntAct=EBI-1753081, EBI-1753081;
CC O43918; Q9UER7: DAXX; NbExp=5; IntAct=EBI-1753081, EBI-77321;
CC O43918; P68431: H3C12; NbExp=20; IntAct=EBI-1753081, EBI-79722;
CC O43918; P16333: NCK1; NbExp=2; IntAct=EBI-1753081, EBI-389883;
CC O43918; P78527: PRKDC; NbExp=2; IntAct=EBI-1753081, EBI-352053;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:14974083,
CC ECO:0000269|PubMed:26084028}. Cytoplasm {ECO:0000269|PubMed:11274163,
CC ECO:0000269|PubMed:14974083}. Note=Predominantly nuclear but also
CC cytoplasmic (PubMed:11274163, PubMed:14974083). Found in nuclear body-
CC like structures (dots) and in a filamentous vimentin-like pattern
CC (PubMed:11274163, PubMed:14974083, PubMed:26084028). Associated with
CC tubular structures (PubMed:11274163, PubMed:14974083).
CC {ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:14974083,
CC ECO:0000269|PubMed:26084028}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Comment=Additional isoforms seem to exist. Experimental confirmation
CC may be lacking for some isoforms.;
CC Name=1; Synonyms=AIRE-1;
CC IsoId=O43918-1; Sequence=Displayed;
CC Name=2; Synonyms=AIRE-2;
CC IsoId=O43918-2; Sequence=VSP_004089;
CC Name=3; Synonyms=AIRE-3;
CC IsoId=O43918-3; Sequence=VSP_004089, VSP_004090;
CC Name=4;
CC IsoId=O43918-4; Sequence=VSP_004089, VSP_043529;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in
CC thymus (medullary epithelial cells and monocyte-dendritic cells),
CC pancreas, adrenal cortex and testis. Expressed at lower level in the
CC spleen, fetal liver and lymph nodes. In secondary lymphoid organs,
CC expressed in a discrete population of bone marrow-derived toleregenic
CC antigen presenting cells (APCs) called extrathymic AIRE expressing
CC cells (eTAC)(at protein level) (PubMed:23993652). Isoform 2 and isoform
CC 3 seem to be less frequently expressed than isoform 1, if at all.
CC {ECO:0000269|PubMed:23993652}.
CC -!- DOMAIN: The L-X-X-L-L repeats may be implicated in binding to nuclear
CC receptors.
CC -!- DOMAIN: The HSR domain is required for localization on tubular
CC structures (N-terminal part) and for homodimerization.
CC -!- DOMAIN: Interacts via the first PHD domain with the N-terminus of
CC histone H3 that is not methylated at 'Lys-4'. Disruption of the first
CC PHD domain has been shown to lead to reduced transcriptional activity
CC and to localization of the protein mainly in the cytoplasm in small
CC granules. While the PHD zinc fingers are necessary for the
CC transactivation capacity of the protein, other regions also modulate
CC this function.
CC -!- PTM: Phosphorylated. Phosphorylation could trigger oligomerization.
CC {ECO:0000269|PubMed:11533054}.
CC -!- DISEASE: Autoimmune polyendocrine syndrome 1, with or without
CC reversible metaphyseal dysplasia (APS1) [MIM:240300]: A rare disease
CC characterized by the combination of chronic mucocutaneous candidiasis,
CC hypoparathyroidism and Addison disease. Symptoms of mucocutaneous
CC candidiasis manifest first, followed by hypotension or fatigue
CC occurring as a result of Addison disease. APS1 is associated with other
CC autoimmune disorders including diabetes mellitus, vitiligo, alopecia,
CC hepatitis, pernicious anemia and primary hypothyroidism.
CC {ECO:0000269|PubMed:10677297, ECO:0000269|PubMed:11274163,
CC ECO:0000269|PubMed:11275943, ECO:0000269|PubMed:11524731,
CC ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11600535,
CC ECO:0000269|PubMed:11836330, ECO:0000269|PubMed:12050215,
CC ECO:0000269|PubMed:12173302, ECO:0000269|PubMed:12625412,
CC ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15649886,
CC ECO:0000269|PubMed:15712268, ECO:0000269|PubMed:16114041,
CC ECO:0000269|PubMed:18292755, ECO:0000269|PubMed:19446523,
CC ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947,
CC ECO:0000269|PubMed:9398839, ECO:0000269|PubMed:9888391}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Most of the mutations alter the nucleus-cytoplasm distribution
CC of AIRE and disturb its association with nuclear dots and cytoplasmic
CC filaments. Most of the mutations also decrease transactivation of the
CC protein. The HSR domain is responsible for the homomultimerization
CC activity of AIRE. All the missense mutations of the HSR and the SAND
CC domains decrease this activity, but those in other domains do not. The
CC AIRE protein is present in soluble high-molecular-weight complexes.
CC Mutations in the HSR domain and deletion of PHD zinc fingers disturb
CC the formation of these complexes (PubMed:14974083). Heterozygous
CC mutations within the PHD1 domain have dominant-negative effects and
CC cause organ-specific autoimmune diseases (PubMed:26084028). Patients
CC harbor extremely high-affinity, neutralizing autoantibodies,
CC particularly against specific cytokines such as type I interferons
CC which could protect them from some types of autoimmune diseases, like
CC type I diabetes (PubMed:27426947). {ECO:0000269|PubMed:14974083,
CC ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947}.
CC -!- WEB RESOURCE: Name=AIREbase; Note=AIRE mutation db;
CC URL="http://structure.bmc.lu.se/idbase/AIREbase/";
CC -!- WEB RESOURCE: Name=Mendelian genes autoimmune regulator (AIRE);
CC Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/AIRE";
CC ---------------------------------------------------------------------------
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DR EMBL; AB006682; BAA23988.1; -; mRNA.
DR EMBL; AB006683; BAA23989.1; -; mRNA.
DR EMBL; AB006684; BAA23990.1; -; Genomic_DNA.
DR EMBL; AB006684; BAA23991.1; -; Genomic_DNA.
DR EMBL; AB006684; BAA23992.1; -; Genomic_DNA.
DR EMBL; AB006685; BAA23993.1; -; mRNA.
DR EMBL; Z97990; CAB10790.1; -; mRNA.
DR EMBL; AJ009610; CAA08759.1; -; Genomic_DNA.
DR EMBL; AP001754; BAA95560.1; -; Genomic_DNA.
DR EMBL; AP001060; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09443.1; -; Genomic_DNA.
DR EMBL; BC137268; AAI37269.1; -; mRNA.
DR EMBL; BC137270; AAI37271.1; -; mRNA.
DR CCDS; CCDS13706.1; -. [O43918-1]
DR RefSeq; NP_000374.1; NM_000383.3. [O43918-1]
DR PDB; 1XWH; NMR; -; A=293-354.
DR PDB; 2KE1; NMR; -; A=293-354.
DR PDB; 2KFT; NMR; -; A=294-347.
DR PDB; 2LRI; NMR; -; C=423-485.
DR PDBsum; 1XWH; -.
DR PDBsum; 2KE1; -.
DR PDBsum; 2KFT; -.
DR PDBsum; 2LRI; -.
DR AlphaFoldDB; O43918; -.
DR BMRB; O43918; -.
DR SMR; O43918; -.
DR BioGRID; 106823; 101.
DR CORUM; O43918; -.
DR DIP; DIP-47504N; -.
DR IntAct; O43918; 35.
DR MINT; O43918; -.
DR STRING; 9606.ENSP00000291582; -.
DR iPTMnet; O43918; -.
DR PhosphoSitePlus; O43918; -.
DR BioMuta; AIRE; -.
DR EPD; O43918; -.
DR MassIVE; O43918; -.
DR PaxDb; O43918; -.
DR PeptideAtlas; O43918; -.
DR PRIDE; O43918; -.
DR Antibodypedia; 10157; 649 antibodies from 43 providers.
DR DNASU; 326; -.
DR Ensembl; ENST00000291582.6; ENSP00000291582.5; ENSG00000160224.17. [O43918-1]
DR GeneID; 326; -.
DR KEGG; hsa:326; -.
DR MANE-Select; ENST00000291582.6; ENSP00000291582.5; NM_000383.4; NP_000374.1.
DR UCSC; uc002zei.4; human. [O43918-1]
DR CTD; 326; -.
DR DisGeNET; 326; -.
DR GeneCards; AIRE; -.
DR HGNC; HGNC:360; AIRE.
DR HPA; ENSG00000160224; Tissue enhanced (brain, lymphoid tissue).
DR MalaCards; AIRE; -.
DR MIM; 109100; phenotype.
DR MIM; 240300; phenotype.
DR MIM; 607358; gene.
DR neXtProt; NX_O43918; -.
DR OpenTargets; ENSG00000160224; -.
DR Orphanet; 3453; Autoimmune polyendocrinopathy type 1.
DR Orphanet; 189466; Familial isolated hypoparathyroidism due to impaired PTH secretion.
DR PharmGKB; PA24654; -.
DR VEuPathDB; HostDB:ENSG00000160224; -.
DR eggNOG; KOG0383; Eukaryota.
DR GeneTree; ENSGT00940000161104; -.
DR HOGENOM; CLU_042233_1_0_1; -.
DR InParanoid; O43918; -.
DR OMA; GIHKAMY; -.
DR OrthoDB; 1203363at2759; -.
DR PhylomeDB; O43918; -.
DR TreeFam; TF336193; -.
DR PathwayCommons; O43918; -.
DR SignaLink; O43918; -.
DR SIGNOR; O43918; -.
DR BioGRID-ORCS; 326; 11 hits in 1089 CRISPR screens.
DR EvolutionaryTrace; O43918; -.
DR GeneWiki; Autoimmune_regulator; -.
DR GenomeRNAi; 326; -.
DR Pharos; O43918; Tbio.
DR PRO; PR:O43918; -.
DR Proteomes; UP000005640; Chromosome 21.
DR RNAct; O43918; protein.
DR Bgee; ENSG00000160224; Expressed in hypothalamus and 77 other tissues.
DR Genevisible; O43918; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0001674; C:female germ cell nucleus; IEA:Ensembl.
DR GO; GO:0001673; C:male germ cell nucleus; IEA:Ensembl.
DR GO; GO:0016604; C:nuclear body; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0045182; F:translation regulator activity; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0002509; P:central tolerance induction to self antigen; IMP:UniProtKB.
DR GO; GO:0006959; P:humoral immune response; IBA:GO_Central.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0045060; P:negative thymic T cell selection; IBA:GO_Central.
DR GO; GO:0002458; P:peripheral T cell tolerance induction; ISS:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:NTNU_SB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:2000410; P:regulation of thymocyte migration; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0097536; P:thymus epithelium morphogenesis; ISS:UniProtKB.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR CDD; cd15540; PHD2_AIRE; 1.
DR Gene3D; 3.10.390.10; -; 1.
DR Gene3D; 3.30.40.10; -; 2.
DR InterPro; IPR008087; AIRE.
DR InterPro; IPR042580; AIRE_PHD2.
DR InterPro; IPR004865; HSR_dom.
DR InterPro; IPR010919; SAND-like_dom_sf.
DR InterPro; IPR000770; SAND_dom.
DR InterPro; IPR019786; Zinc_finger_PHD-type_CS.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR001965; Znf_PHD.
DR InterPro; IPR019787; Znf_PHD-finger.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF03172; HSR; 1.
DR Pfam; PF00628; PHD; 1.
DR Pfam; PF01342; SAND; 1.
DR PRINTS; PR01711; AIREGULATOR.
DR SMART; SM00249; PHD; 2.
DR SMART; SM00258; SAND; 1.
DR SUPFAM; SSF57903; SSF57903; 2.
DR SUPFAM; SSF63763; SSF63763; 1.
DR PROSITE; PS51414; HSR; 1.
DR PROSITE; PS50864; SAND; 1.
DR PROSITE; PS01359; ZF_PHD_1; 2.
DR PROSITE; PS50016; ZF_PHD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Cytoplasm;
KW Direct protein sequencing; Disease variant; DNA-binding; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Transcription;
KW Transcription regulation; Zinc; Zinc-finger.
FT CHAIN 1..545
FT /note="Autoimmune regulator"
FT /id="PRO_0000064513"
FT DOMAIN 1..105
FT /note="HSR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00747"
FT DOMAIN 181..280
FT /note="SAND"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00185"
FT ZN_FING 296..343
FT /note="PHD-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146"
FT ZN_FING 434..475
FT /note="PHD-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146"
FT REGION 101..178
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 234..290
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 295..298
FT /note="Interaction with histone H3 not methylated at 'Lys-
FT 4'"
FT REGION 304..312
FT /note="Interaction with histone H3 not methylated at 'Lys-
FT 4'"
FT REGION 331..335
FT /note="Interaction with histone H3 not methylated at 'Lys-
FT 4'"
FT REGION 348..382
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 489..508
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 7..11
FT /note="LXXLL motif 1"
FT MOTIF 63..67
FT /note="LXXLL motif 2"
FT MOTIF 414..418
FT /note="LXXLL motif 3"
FT MOTIF 516..520
FT /note="LXXLL motif 4"
FT VAR_SEQ 1..292
FT /note="MATDAALRRLLRLHRTEIAVAVDSAFPLLHALADHDVVPEDKFQETLHLKEK
FT EGCPQAFHALLSWLLTQDSTAILDFWRVLFKDYNLERYGRLQPILDSFPKDVDLSQPRK
FT GRKPPAVPKALVPPPRLPTKRKASEEARAAAPAALTPRGTASPGSQLKAKPPKKPESSA
FT EQQRLPLGNGIQTMSASVQRAVAMSSGDVPGARGAVEGILIQQVFESGGSKKCIQVGGE
FT FYTPSKFEDSGSGKNKARSSSGPKPLVRAKGAQGAAPGGGEARLGQQGSVPAPLALPSD
FT PQLH -> MWLVYSSGAPGTQQPARNRVFFPIGMAPGGVCWRPDGWGTGGQGRISGPGS
FT MGAGQRLGSSGTQRCCWGSCFGKEVALRRVLHPS (in isoform 2, isoform 3
FT and isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9398839"
FT /id="VSP_004089"
FT VAR_SEQ 293
FT /note="Q -> PVCMGVSCLCQ (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_043529"
FT VAR_SEQ 377..545
FT /note="VRGPPGEPLAGMDTTLVYKHLPAPPSAAPLPGLDSSALHPLLCVGPEGQQNL
FT APGARCGVCGDGTDVLRCTHCAAAFHWRCHFPAGTSRPGTGLRCRSCSGDVTPAPVEGV
FT LAPSPARLAPGPAKDDTASHEPALHRDDLESLLSEHTFDGILQWAIQSMARPAAPFPS
FT -> PRCQGWTPRPCTPYCVWVLRVSRTWLLVRVAGCAEMVRTCCGVLTAPLPSTGAATS
FT QPAPPGPGRACAADPAQET (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9398839"
FT /id="VSP_004090"
FT VARIANT 15
FT /note="R -> C (in APS1; dbSNP:rs179363875)"
FT /evidence="ECO:0000269|PubMed:12625412"
FT /id="VAR_026480"
FT VARIANT 15
FT /note="R -> L (in APS1; prevents homooligomerization;
FT slightly alters subcellular localization; no effect on the
FT transcriptional transactivation activity;
FT dbSNP:rs179363876)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15712268"
FT /id="VAR_013713"
FT VARIANT 16
FT /note="T -> M (in APS1; prevents homooligomerization;
FT slightly alters subcellular localization; no effect on the
FT transcriptional transactivation activity;
FT dbSNP:rs179363877)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:14974083,
FT ECO:0000269|PubMed:15712268"
FT /id="VAR_013714"
FT VARIANT 21
FT /note="A -> V (in APS1; no effect on homooligomerization;
FT no effect on subcellular localization; no effect on the
FT transcriptional transactivation activity;
FT dbSNP:rs179363886)"
FT /evidence="ECO:0000269|PubMed:12050215,
FT ECO:0000269|PubMed:14974083"
FT /id="VAR_026481"
FT VARIANT 22..23
FT /note="Missing (in APS1; prevents homodimerization)"
FT /evidence="ECO:0000269|PubMed:15712268"
FT /id="VAR_026482"
FT VARIANT 28
FT /note="L -> P (in APS1; abolishes association with
FT cytoplasmic tubular structures and homodimerization; loss
FT of doted nuclear localization; nuclear smear; severe
FT decrease of transcriptional transactivation activity;
FT dbSNP:rs179363878)"
FT /evidence="ECO:0000269|PubMed:11274163,
FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083,
FT ECO:0000269|PubMed:16114041, ECO:0000269|PubMed:26084028,
FT ECO:0000269|PubMed:9888391"
FT /id="VAR_005004"
FT VARIANT 29
FT /note="L -> P (in APS1; dbSNP:rs179363879)"
FT /evidence="ECO:0000269|PubMed:12173302,
FT ECO:0000269|PubMed:14974083"
FT /id="VAR_013715"
FT VARIANT 77
FT /note="F -> S (in APS1; loss of homooligomerization;
FT dbSNP:rs179363887)"
FT /evidence="ECO:0000269|PubMed:15712268"
FT /id="VAR_026483"
FT VARIANT 78
FT /note="W -> R (in APS1; loss of homooligomerization;
FT dbSNP:rs179363880)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11836330,
FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15712268"
FT /id="VAR_013716"
FT VARIANT 80
FT /note="V -> L (in APS1; dbSNP:rs179363881)"
FT /evidence="ECO:0000269|PubMed:10677297,
FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083"
FT /id="VAR_013717"
FT VARIANT 83
FT /note="K -> E (in APS1; dbSNP:rs121434255)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:9398839"
FT /id="VAR_005005"
FT VARIANT 85
FT /note="Y -> C (in APS1; no significant effect on
FT transcriptional transactivation activity;
FT dbSNP:rs179363882)"
FT /evidence="ECO:0000269|PubMed:10677297,
FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:12050215,
FT ECO:0000269|PubMed:16114041"
FT /id="VAR_013718"
FT VARIANT 90
FT /note="Y -> C (in APS1; decreases doted nuclear
FT localization; dbSNP:rs179363883)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:26084028"
FT /id="VAR_013719"
FT VARIANT 93
FT /note="L -> R (in APS1; dbSNP:rs179363884)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:14974083"
FT /id="VAR_013720"
FT VARIANT 228
FT /note="G -> W (in APS1; changes the subcellular
FT localization and in addition disrupts the transactivating
FT capacity of the wild-type AIRE; acts with a dominant
FT negative effect by binding to the wild-type AIRE thus
FT preventing the protein from forming the complexes needed
FT for transactivation; dbSNP:rs121434257)"
FT /evidence="ECO:0000269|PubMed:11600535,
FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:16114041"
FT /id="VAR_014422"
FT VARIANT 252
FT /note="P -> L (in APS1; benign variant; does not affect
FT transcriptional transactivation activity;
FT dbSNP:rs34397615)"
FT /evidence="ECO:0000269|PubMed:11836330,
FT ECO:0000269|PubMed:16114041"
FT /id="VAR_026484"
FT VARIANT 278
FT /note="S -> R (in dbSNP:rs1800520)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:12625412, ECO:0000269|PubMed:9717837"
FT /id="VAR_005006"
FT VARIANT 298
FT /note="E -> K (in dbSNP:rs763636007)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076940"
FT VARIANT 299
FT /note="C -> W (in dbSNP:rs751066946)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076941"
FT VARIANT 301
FT /note="V -> M (in APS1; no effect on protein structure or
FT on interaction with histone H3; no effect on doted nuclear
FT localization; dominant-negative effect on regulation of
FT target gene transcription; dbSNP:rs150634562)"
FT /evidence="ECO:0000269|PubMed:11524731,
FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755,
FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028"
FT /id="VAR_013721"
FT VARIANT 302
FT /note="C -> Y (found in patients with hypothyroidism and
FT organ- and cytokine-specific autoantibodies; no effect on
FT doted nuclear localization; dominant-negative effect on
FT regulation of target gene transcription)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076942"
FT VARIANT 303
FT /note="R -> Q (in dbSNP:rs139808903)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076943"
FT VARIANT 303
FT /note="R -> W (in dbSNP:rs778929451)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076944"
FT VARIANT 305
FT /note="G -> S (found in a patient with pernicious anemia
FT and neuropathy; unknown pathological significance; no
FT effect on doted nuclear localization; dominant-negative
FT effect on regulation of target gene transcription)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_013722"
FT VARIANT 306
FT /note="G -> R (in dbSNP:rs754932526)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076945"
FT VARIANT 309
FT /note="I -> M (in dbSNP:rs74162062)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076946"
FT VARIANT 311
FT /note="C -> Y (in APS1; impairs zinc binding and folding of
FT the PHD-type 1 zinc finger; dominant-negative effect on the
FT regulation of target gene transcription; no effect on doted
FT nuclear localization; dominant-negative effect on
FT regulation of target gene transcription;
FT dbSNP:rs386833674)"
FT /evidence="ECO:0000269|PubMed:10677297,
FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:12050215,
FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755,
FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028"
FT /id="VAR_013723"
FT VARIANT 316
FT /note="R -> Q (in dbSNP:rs202027254)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076947"
FT VARIANT 316
FT /note="R -> W (unknown pathological significance; found in
FT a patient with pernicious anemia; dbSNP:rs139874934)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076948"
FT VARIANT 319
FT /note="H -> P (in dbSNP:rs776951380)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076949"
FT VARIANT 326
FT /note="P -> L (in APS1; no significant effect on structure,
FT but may alter protein interactions; no effect on doted
FT nuclear localization; dominant-negative effect on
FT regulation of target gene transcription;
FT dbSNP:rs179363885)"
FT /evidence="ECO:0000269|PubMed:11275943,
FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028"
FT /id="VAR_026485"
FT VARIANT 326
FT /note="P -> Q (in APS1; alters folding of the PHD-type 1
FT zinc finger; dbSNP:rs179363885)"
FT /evidence="ECO:0000269|PubMed:10677297,
FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083,
FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:19446523"
FT /id="VAR_013724"
FT VARIANT 328
FT /note="R -> Q (found in a patient with acrofacial vitiligo
FT and gastric parietal cell autoantibodies; no effect on
FT doted nuclear localization; dominant-negative effect on
FT regulation of target gene transcription;
FT dbSNP:rs775921321)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076950"
FT VARIANT 328
FT /note="R -> W (in dbSNP:rs74162063)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076951"
FT VARIANT 332
FT /note="S -> R (in dbSNP:rs766901260)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076952"
FT VARIANT 484
FT /note="V -> A (found in a patient with acrofacial vitiligo
FT and gastric parietal cell autoantibodies; unknown
FT pathological significance; dbSNP:rs769470638)"
FT /evidence="ECO:0000269|PubMed:26084028"
FT /id="VAR_076953"
FT VARIANT 539
FT /note="P -> L (in APS1; dbSNP:rs179363889)"
FT /evidence="ECO:0000269|PubMed:11836330"
FT /id="VAR_026486"
FT MUTAGEN 28..29
FT /note="LL->PP: Loss of doted nuclear location, forms
FT nuclear smears. Loss of transactivation activity on target
FT genes transcription."
FT /evidence="ECO:0000269|PubMed:26084028"
FT MUTAGEN 97
FT /note="L->P: Loss of transactivation activity on target
FT gene transcription; no dominant-negative effect on target
FT gene transcription. Loss of doted nuclear localization."
FT /evidence="ECO:0000269|PubMed:26084028"
FT MUTAGEN 295
FT /note="N->A: Abolishes interaction with histone H3."
FT /evidence="ECO:0000269|PubMed:19293276"
FT MUTAGEN 297
FT /note="D->A: Strongly reduces interaction with unmethylated
FT histone H3 and abolishes interaction with histone H3
FT trimethylated at 'Lys-4'. No effect on doted nuclear
FT localization. Dominant-negative effect on target gene
FT transcription."
FT /evidence="ECO:0000269|PubMed:18292755,
FT ECO:0000269|PubMed:26084028"
FT MUTAGEN 298
FT /note="E->A: Reduces interaction with histone H3."
FT /evidence="ECO:0000269|PubMed:19293276"
FT MUTAGEN 302
FT /note="C->P: Reduces transcriptional activation."
FT /evidence="ECO:0000269|PubMed:11274163"
FT MUTAGEN 303
FT /note="R->P: Alters protein folding and abolishes
FT interaction with histone H3. No effect on doted nuclear
FT localization. Dominant-negative effect on target gene
FT transcription."
FT /evidence="ECO:0000269|PubMed:19293276,
FT ECO:0000269|PubMed:26084028"
FT MUTAGEN 304
FT /note="D->A: Strongly reduces interaction with histone H3."
FT /evidence="ECO:0000269|PubMed:19293276"
FT MUTAGEN 307
FT /note="E->A: Reduces interaction with histone H3."
FT /evidence="ECO:0000269|PubMed:19293276"
FT MUTAGEN 312
FT /note="D->A: Abolishes interaction with histone H3."
FT /evidence="ECO:0000269|PubMed:18292755"
FT MUTAGEN 312
FT /note="D->N: No effect on doted nuclear localization.
FT Dominant-negative effect on target gene transcription."
FT /evidence="ECO:0000269|PubMed:26084028"
FT MUTAGEN 437
FT /note="C->P: Reduces transcription activation."
FT /evidence="ECO:0000269|PubMed:11274163"
FT MUTAGEN 446
FT /note="C->G: Dominant-negative effect on regulation of
FT target gene transcription."
FT /evidence="ECO:0000269|PubMed:26084028"
FT MUTAGEN 471
FT /note="R->C: No effect on regulation of target gene
FT transcription."
FT /evidence="ECO:0000269|PubMed:26084028"
FT CONFLICT 437..467
FT /note="CGDGTDVLRCTHCAAAFHWRCHFPAGTSRPG -> W (in Ref. 3;
FT CAA08759)"
FT /evidence="ECO:0000305"
FT STRAND 298..303
FT /evidence="ECO:0007829|PDB:1XWH"
FT STRAND 306..310
FT /evidence="ECO:0007829|PDB:2KE1"
FT STRAND 312..314
FT /evidence="ECO:0007829|PDB:2KE1"
FT STRAND 317..319
FT /evidence="ECO:0007829|PDB:2KE1"
FT TURN 320..322
FT /evidence="ECO:0007829|PDB:1XWH"
FT STRAND 323..325
FT /evidence="ECO:0007829|PDB:1XWH"
FT HELIX 338..342
FT /evidence="ECO:0007829|PDB:1XWH"
FT TURN 423..426
FT /evidence="ECO:0007829|PDB:2LRI"
FT TURN 435..437
FT /evidence="ECO:0007829|PDB:2LRI"
FT STRAND 447..449
FT /evidence="ECO:0007829|PDB:2LRI"
FT HELIX 455..458
FT /evidence="ECO:0007829|PDB:2LRI"
FT TURN 460..462
FT /evidence="ECO:0007829|PDB:2LRI"
FT STRAND 467..469
FT /evidence="ECO:0007829|PDB:2LRI"
FT TURN 473..476
FT /evidence="ECO:0007829|PDB:2LRI"
SQ SEQUENCE 545 AA; 57727 MW; 8CF703F8C9411BC5 CRC64;
MATDAALRRL LRLHRTEIAV AVDSAFPLLH ALADHDVVPE DKFQETLHLK EKEGCPQAFH
ALLSWLLTQD STAILDFWRV LFKDYNLERY GRLQPILDSF PKDVDLSQPR KGRKPPAVPK
ALVPPPRLPT KRKASEEARA AAPAALTPRG TASPGSQLKA KPPKKPESSA EQQRLPLGNG
IQTMSASVQR AVAMSSGDVP GARGAVEGIL IQQVFESGGS KKCIQVGGEF YTPSKFEDSG
SGKNKARSSS GPKPLVRAKG AQGAAPGGGE ARLGQQGSVP APLALPSDPQ LHQKNEDECA
VCRDGGELIC CDGCPRAFHL ACLSPPLREI PSGTWRCSSC LQATVQEVQP RAEEPRPQEP
PVETPLPPGL RSAGEEVRGP PGEPLAGMDT TLVYKHLPAP PSAAPLPGLD SSALHPLLCV
GPEGQQNLAP GARCGVCGDG TDVLRCTHCA AAFHWRCHFP AGTSRPGTGL RCRSCSGDVT
PAPVEGVLAP SPARLAPGPA KDDTASHEPA LHRDDLESLL SEHTFDGILQ WAIQSMARPA
APFPS
