View source for 1xwh


==NMR structure of the first phd finger of autoimmune regulator protein (AIRE1): insights into apeced==
<StructureSection load='1xwh' size='340' side='right'caption='[[1xwh]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1xwh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XWH FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xwh OCA], [https://pdbe.org/1xwh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xwh RCSB], [https://www.ebi.ac.uk/pdbsum/1xwh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xwh ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN] Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:[https://omim.org/entry/240300 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.<ref>PMID:18292755</ref> <ref>PMID:10677297</ref> <ref>PMID:11274163</ref> <ref>PMID:14974083</ref> <ref>PMID:9398839</ref> <ref>PMID:15649886</ref> <ref>PMID:19446523</ref> <ref>PMID:9888391</ref> <ref>PMID:11275943</ref> <ref>PMID:11524731</ref> <ref>PMID:11524733</ref> <ref>PMID:11600535</ref> <ref>PMID:12173302</ref> <ref>PMID:12625412</ref> <ref>PMID:11836330</ref> <ref>PMID:12050215</ref> <ref>PMID:15712268</ref> <ref>PMID:16114041</ref>   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 ==
[https://www.uniprot.org/uniprot/AIRE_HUMAN 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.<ref>PMID:18292755</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xw/1xwh_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1xwh ConSurf].
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== Publication Abstract from PubMed ==
Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease.,Bottomley MJ, Stier G, Pennacchini D, Legube G, Simon B, Akhtar A, Sattler M, Musco G J Biol Chem. 2005 Mar 25;280(12):11505-12. Epub 2005 Jan 13. PMID:15649886<ref>PMID:15649886</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Akhtar A]]
[[Category: Bottomley MJ]]
[[Category: Krasotkina J]]
[[Category: Legube G]]
[[Category: Musco G]]
[[Category: Sattler M]]
[[Category: Simon B]]
[[Category: Stier G]]