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| | ==The RUNX1 Runt domain at 1.25A resolution: A structural switch and specifically bound chloride ions modulate DNA binding== | | ==The RUNX1 Runt domain at 1.25A resolution: A structural switch and specifically bound chloride ions modulate DNA binding== |
| - | <StructureSection load='1eaq' size='340' side='right' caption='[[1eaq]], [[Resolution|resolution]] 1.25Å' scene=''> | + | <StructureSection load='1eaq' size='340' side='right'caption='[[1eaq]], [[Resolution|resolution]] 1.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1eaq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EAQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1EAQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1eaq]] 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=1EAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EAQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cmo|1cmo]], [[1co1|1co1]], [[1ean|1ean]], [[1eao|1eao]], [[1e50|1e50]], [[1h9d|1h9d]], [[1hjb|1hjb]], [[1hjc|1hjc]], [[1io4|1io4]]</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=1eaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eaq OCA], [https://pdbe.org/1eaq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eaq RCSB], [https://www.ebi.ac.uk/pdbsum/1eaq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eaq ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1eaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eaq OCA], [http://pdbe.org/1eaq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1eaq RCSB], [http://www.ebi.ac.uk/pdbsum/1eaq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1eaq ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://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. | + | [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 == | | == Function == |
| - | [[http://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> | + | [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 == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ea/1eaq_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ea/1eaq_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Backstrom, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Grundstrom, C]] | + | [[Category: Mus musculus]] |
| - | [[Category: Grundstrom, T]] | + | [[Category: Backstrom S]] |
| - | [[Category: Hard, T]] | + | [[Category: Grundstrom C]] |
| - | [[Category: Sauer, U H]] | + | [[Category: Grundstrom T]] |
| - | [[Category: Wolf-Watz, M]] | + | [[Category: Hard T]] |
| - | [[Category: Acute myeloid leukemia]] | + | [[Category: Sauer UH]] |
| - | [[Category: Aml]] | + | [[Category: Wolf-Watz M]] |
| - | [[Category: Chloride binding]]
| + | |
| - | [[Category: Ig fold]]
| + | |
| - | [[Category: Runt domain]]
| + | |
| - | [[Category: Runx1]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| - | [[Category: Transcription/dna]]
| + | |
| Structural highlights
Disease
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
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).[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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:12217689[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell. 1996 Jan 26;84(2):321-30. PMID:8565077
- ↑ Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9. PMID:8622955
- ↑ Backstrom S, Wolf-Watz M, Grundstrom C, Hard T, Grundstrom T, Sauer UH. The RUNX1 Runt domain at 1.25A resolution: a structural switch and specifically bound chloride ions modulate DNA binding. J Mol Biol. 2002 Sep 13;322(2):259-72. PMID:12217689
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