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| - | ==R164N MUTANT OF THE RUNX1 RUNT DOMAIN== | + | |
| - | <StructureSection load='2j6w' size='340' side='right' caption='[[2j6w]], [[Resolution|resolution]] 2.60Å' scene=''> | + | ==R164N mutant of the RUNX1 Runt domain== |
| | + | <StructureSection load='2j6w' size='340' side='right'caption='[[2j6w]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2j6w]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J6W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2J6W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2j6w]] 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=2J6W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J6W 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]] 2.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ean|1ean]], [[1eao|1eao]], [[1eaq|1eaq]], [[1hjb|1hjb]], [[1hjc|1hjc]], [[1io4|1io4]]</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></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=2j6w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j6w OCA], [http://pdbe.org/2j6w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2j6w RCSB], [http://www.ebi.ac.uk/pdbsum/2j6w PDBsum]</span></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=2j6w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j6w OCA], [https://pdbe.org/2j6w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j6w RCSB], [https://www.ebi.ac.uk/pdbsum/2j6w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j6w 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/j6/2j6w_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j6/2j6w_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Bielnicka, I]] | + | [[Category: Mus musculus]] |
| - | [[Category: Bushweller, J H]] | + | [[Category: Bielnicka I]] |
| - | [[Category: Grembecka, J]] | + | [[Category: Bushweller JH]] |
| - | [[Category: Liu, Y]] | + | [[Category: Grembecka J]] |
| - | [[Category: Lukasik, S M]] | + | [[Category: Liu Y]] |
| - | [[Category: Speck, N A]] | + | [[Category: Lukasik SM]] |
| - | [[Category: Zhe, L]] | + | [[Category: Speck NA]] |
| - | [[Category: Acute myeloid leukemia]]
| + | [[Category: Zhe L]] |
| - | [[Category: Aml]]
| + | |
| - | [[Category: Chloride binding]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Ig fold]]
| + | |
| - | [[Category: Nuclear protein]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Runt domain]]
| + | |
| - | [[Category: Runx1]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[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 Runt domain is the DNA binding domain of the core binding factor (CBF) Runx subunits. The CBFs are transcription factors that play critical roles in hematopoiesis, bone, and neuron development in mammals. A common non-DNA binding CBFbeta subunit heterodimerizes with the Runt domain of the Runx proteins and allosterically regulates its affinity for DNA. Previous NMR dynamics studies suggested a model whereby CBFbeta allosterically regulates DNA binding by quenching conformational exchange in the Runt domain, particularly in the S-switch region and the betaE'-F loop. We sought to test this model, and to this end introduced all possible single amino acid substitutions into the S-switch region and the betaE'-F loop, and screened for mutations that enhanced DNA-binding. We demonstrate that one Runt domain mutant, R164N, binds both DNA and CBFbeta with higher affinity, but it is less sensitive to allosteric regulation by CBFbeta. Analysis of NMR relaxation data shows that the chemical exchange exhibited by the wild-type Runt domain is largely quenched by the R164N substitution. These data support a model in which the dynamic behavior of a network of residues connecting the CBFbeta and DNA binding sites on the Runt domain plays a critical role in the mechanism of allosteric regulation. This study provides an important functional link between dynamic behavior and protein allosteric function, consistent with results on other allosterically regulated proteins.
A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFbeta regulation.,Li Z, Lukasik SM, Liu Y, Grembecka J, Bielnicka I, Bushweller JH, Speck NA J Mol Biol. 2006 Dec 15;364(5):1073-83. Epub 2006 Oct 4. PMID:17059830[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
- ↑ Li Z, Lukasik SM, Liu Y, Grembecka J, Bielnicka I, Bushweller JH, Speck NA. A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFbeta regulation. J Mol Biol. 2006 Dec 15;364(5):1073-83. Epub 2006 Oct 4. PMID:17059830 doi:10.1016/j.jmb.2006.10.002
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