View source for 2kft


==NMR Solution structure of the first PHD finger domain of human Autoimmune Regulator (AIRE) in complex with Histone H3(1-20Cys) Peptide==
<StructureSection load='2kft' size='340' side='right'caption='[[2kft]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2kft]] is a 2 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=2KFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KFT 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=2kft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kft OCA], [https://pdbe.org/2kft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kft RCSB], [https://www.ebi.ac.uk/pdbsum/2kft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kft 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/kf/2kft_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=2kft ConSurf].
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== Publication Abstract from PubMed ==
Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.

Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.,Chakravarty S, Zeng L, Zhou MM Structure. 2009 May 13;17(5):670-9. PMID:19446523<ref>PMID:19446523</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2kft" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chakravarty S]]
[[Category: Zeng L]]
[[Category: Zhou M]]