2ke1

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{{STRUCTURE_2ke1| PDB=2ke1 | SCENE= }}
 
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===Molecular Basis of non-modified histone H3 tail Recognition by the First PHD Finger of Autoimmune Regulator===
 
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{{ABSTRACT_PUBMED_19293276}}
 
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==Disease==
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==Molecular Basis of non-modified histone H3 tail Recognition by the First PHD Finger of Autoimmune Regulator==
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[[http://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN]] Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:[http://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.
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<StructureSection load='2ke1' size='340' side='right'caption='[[2ke1]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2ke1]] 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=2KE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KE1 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ke1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ke1 OCA], [https://pdbe.org/2ke1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ke1 RCSB], [https://www.ebi.ac.uk/pdbsum/2ke1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ke1 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ke/2ke1_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2ke1 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus.
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==Function==
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The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation.,Chignola F, Gaetani M, Rebane A, Org T, Mollica L, Zucchelli C, Spitaleri A, Mannella V, Peterson P, Musco G Nucleic Acids Res. 2009 May;37(9):2951-61. Epub 2009 Mar 17. PMID:19293276<ref>PMID:19293276</ref>
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[[http://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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[2ke1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KE1 OCA].
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</div>
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<div class="pdbe-citations 2ke1" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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<ref group="xtra">PMID:019293276</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Chignola, F.]]
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[[Category: Large Structures]]
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[[Category: Gaetani, M.]]
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[[Category: Chignola F]]
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[[Category: Mannella, V.]]
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[[Category: Gaetani M]]
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[[Category: Mollica, L.]]
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[[Category: Mannella V]]
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[[Category: Musco, G.]]
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[[Category: Mollica L]]
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[[Category: Org, T.]]
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[[Category: Musco G]]
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[[Category: Peterson, P.]]
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[[Category: Org T]]
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[[Category: Rebane, A.]]
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[[Category: Peterson P]]
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[[Category: Spitaleri, A.]]
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[[Category: Rebane A]]
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[[Category: Zucchelli, C.]]
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[[Category: Spitaleri A]]
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[[Category: Aire]]
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[[Category: Zucchelli C]]
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[[Category: Disease mutation]]
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[[Category: Gene regulation]]
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[[Category: Histone h3]]
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[[Category: Metal-binding]]
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[[Category: Nucleus]]
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[[Category: Phd finger]]
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[[Category: Transcription]]
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[[Category: Transcription regulation]]
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[[Category: Zinc-finger]]
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Current revision

Molecular Basis of non-modified histone H3 tail Recognition by the First PHD Finger of Autoimmune Regulator

PDB ID 2ke1

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