2kft

Structural highlights

Disease

[AIRE_HUMAN] Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:240300]. An autosomal recessive 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.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]} Note=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.

Function

[AIRE_HUMAN] 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.^[19]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008 Apr;9(4):370-6. doi: 10.1038/sj.embor.2008.11. Epub 2008 Feb 22. PMID:18292755 doi:10.1038/sj.embor.2008.11
2. ↑ Bjorses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet. 2000 Feb;66(2):378-92. PMID:10677297 doi:10.1086/302765
3. ↑ Pitkanen J, Vahamurto P, Krohn K, Peterson P. Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain. J Biol Chem. 2001 Jun 1;276(22):19597-602. Epub 2001 Mar 26. PMID:11274163 doi:10.1074/jbc.M008322200
4. ↑ Halonen M, Kangas H, Ruppell T, Ilmarinen T, Ollila J, Kolmer M, Vihinen M, Palvimo J, Saarela J, Ulmanen I, Eskelin P. APECED-causing mutations in AIRE reveal the functional domains of the protein. Hum Mutat. 2004 Mar;23(3):245-57. PMID:14974083 doi:10.1002/humu.20003
5. ↑ Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene. Nat Genet. 1997 Dec;17(4):393-8. PMID:9398839 doi:10.1038/ng1297-393
6. ↑ Bottomley MJ, Stier G, Pennacchini D, Legube G, Simon B, Akhtar A, Sattler M, Musco G. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. J Biol Chem. 2005 Mar 25;280(12):11505-12. Epub 2005 Jan 13. PMID:15649886 doi:http://dx.doi.org/10.1074/jbc.M413959200
7. ↑ Chakravarty S, Zeng L, Zhou MM. Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator. Structure. 2009 May 13;17(5):670-9. PMID:19446523 doi:10.1016/j.str.2009.02.017
8. ↑ Heino M, Scott HS, Chen Q, Peterson P, Maebpaa U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K. Mutation analyses of North American APS-1 patients. Hum Mutat. 1999;13(1):69-74. PMID:9888391 doi:<69::AID-HUMU8>3.0.CO;2-6 10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6
9. ↑ Saugier-Veber P, Drouot N, Wolf LM, Kuhn JM, Frebourg T, Lefebvre H. Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Eur J Endocrinol. 2001 Apr;144(4):347-51. PMID:11275943
10. ↑ Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K. APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat. 2001 Sep;18(3):205-11. PMID:11524731 doi:10.1002/humu.1176
11. ↑ Cihakova D, Trebusak K, Heino M, Fadeyev V, Tiulpakov A, Battelino T, Tar A, Halasz Z, Blumel P, Tawfik S, Krohn K, Lebl J, Peterson P. Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED. Hum Mutat. 2001 Sep;18(3):225-32. PMID:11524733 doi:10.1002/humu.1178
12. ↑ Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, Marcocci C. 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. J Clin Endocrinol Metab. 2001 Oct;86(10):4747-52. PMID:11600535
13. ↑ Kogawa K, Kudoh J, Nagafuchi S, Ohga S, Katsuta H, Ishibashi H, Harada M, Hara T, Shimizu N. Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. Clin Immunol. 2002 Jun;103(3 Pt 1):277-83. PMID:12173302
14. ↑ Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S, Yamazaki K, Yamada E, Kanaji Y, Takano K. 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. Endocr J. 2002 Dec;49(6):625-33. PMID:12625412
15. ↑ Meloni A, Perniola R, Faa V, Corvaglia E, Cao A, Rosatelli MC. Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. J Clin Endocrinol Metab. 2002 Feb;87(2):841-6. PMID:11836330
16. ↑ Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. 2002 Jun;87(6):2568-74. PMID:12050215
17. ↑ Meloni A, Fiorillo E, Corda D, Perniola R, Cao A, Rosatelli MC. Two novel mutations of the AIRE protein affecting its homodimerization properties. Hum Mutat. 2005 Mar;25(3):319. PMID:15712268 doi:10.1002/humu.9309
18. ↑ Ilmarinen T, Eskelin P, Halonen M, Ruppell T, Kilpikari R, Torres GD, Kangas H, Ulmanen I. Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Hum Mutat. 2005 Oct;26(4):322-31. PMID:16114041 doi:10.1002/humu.20224
19. ↑ Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008 Apr;9(4):370-6. doi: 10.1038/sj.embor.2008.11. Epub 2008 Feb 22. PMID:18292755 doi:10.1038/sj.embor.2008.11
20. ↑ Chakravarty S, Zeng L, Zhou MM. Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator. Structure. 2009 May 13;17(5):670-9. PMID:19446523 doi:10.1016/j.str.2009.02.017