1eao: Difference between revisions

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-[[Image:1eao.gif|left|200px]]<br />
-<applet load="1eao" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1eao, resolution 1.40&Aring;" />
-'''THE RUNX1 RUNT DOMAIN AT 1.25A RESOLUTION: A STRUCTURAL SWITCH AND SPECIFICALLY BOUND CHLORIDE IONS MODULATE DNA BINDING'''<br />
-==Overview==
+==THE RUNX1 Runt domain at 1.4A resolution: a structural switch and specifically bound chloride ions modulate DNA binding==
-The evolutionarily conserved Runt homology domain is characteristic of the, RUNX family of heterodimeric eukaryotic transcription factors, including, RUNX1, RUNX2 and RUNX3. The genes for RUNX1, also termed acute myeloid, leukemia protein 1, AML1, and its dimerization partner core-binding factor, beta, CBFbeta, are essential for hematopoietic development and are, together the most common targets for gene rearrangements in acute human, leukemias. Here, we describe the crystal structure of the uncomplexed, RUNX1 Runt domain at 1.25A resolution and compare its conformation to, previously published structures in complex with DNA, CBFbeta or both. We, find that complex formation induces significant structural rearrangements, in this immunoglobulin (Ig)-like DNA-binding domain. Most pronounced is, the movement of loop L11, which changes from a closed conformation in the, free Runt structure to an open conformation in the CBFbeta-bound and, DNA-bound forms. This transition, which we refer to as the S-switch, and, accompanying structural movements that affect other parts of the Runt, domain are crucial for sustained DNA binding. The closed to open, transition can be induced by CBFbeta alone; suggesting that one role of, CBFbeta is to trigger the S-switch and to stabilize the Runt domain in a, conformation enhanced for DNA binding.A feature of the Runt domain, hitherto unobserved in any Ig-like DNA-binding domain is the presence of, two specifically bound chloride ions. One chloride ion is coordinated by, amino acid residues that make direct DNA contact. In a series of, electrophoretic mobility-shift analyses, we demonstrate a chloride ion, concentration-dependent stimulation of the DNA-binding activity of Runt in, the physiological range. A comparable DNA-binding stimulation was observed, for negatively charged amino acid residues. This suggests a regulatory, mechanism of RUNX proteins through acidic amino acid residues provided by, activation domains during cooperative interaction with other transcription, factors.
+<StructureSection load='1eao' size='340' side='right'caption='[[1eao]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1eao]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EAO FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</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=1eao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eao OCA], [https://pdbe.org/1eao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eao RCSB], [https://www.ebi.ac.uk/pdbsum/1eao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eao ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/RUNX1_MOUSE RUNX1_MOUSE] Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked.
+== Function ==
+[https://www.uniprot.org/uniprot/RUNX1_MOUSE RUNX1_MOUSE] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL-3 and GM-CSF promoters. Essential for the development of normal hematopoiesis. Isoform 4 shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation (By similarity).<ref>PMID:8565077</ref> <ref>PMID:8622955</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/ea/1eao_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=1eao ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-EAO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with BR as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: BR1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EAO OCA].
+*[[Core-binding factor|Core-binding factor]]
+== References ==
-==Reference==
+<references/>
-The RUNX1 Runt domain at 1.25A resolution: a structural switch and specifically bound chloride ions modulate DNA binding., Backstrom S, Wolf-Watz M, Grundstrom C, Hard T, Grundstrom T, Sauer UH, J Mol Biol. 2002 Sep 13;322(2):259-72. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12217689 12217689]
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Single protein]]
+[[Category: Backstrom S]]
-[[Category: Backstrom, S.]]
+[[Category: Grundstrom C]]
-[[Category: Grundstrom, C.]]
+[[Category: Grundstrom T]]
-[[Category: Grundstrom, T.]]
+[[Category: Hard TH]]
-[[Category: Hard, T.H.]]
+[[Category: Sauer UH]]
-[[Category: Sauer, U.H.]]
+[[Category: Wolf-Watz M]]
-[[Category: Wolf-Watz, M.]]
-[[Category: BR]]
-[[Category: acute myeloid leukemia]]
-[[Category: aml]]
-[[Category: chloride binding]]
-[[Category: ig fold]]
-[[Category: runt domain]]
-[[Category: runx1]]
-[[Category: transcription factor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov  5 13:05:08 2007''