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| | ==Crystal structure of the KANSL1-WDR5-KANSL2 complex.== | | ==Crystal structure of the KANSL1-WDR5-KANSL2 complex.== |
| - | <StructureSection load='4cy2' size='340' side='right' caption='[[4cy2]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4cy2' size='340' side='right'caption='[[4cy2]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cy2]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CY2 OCA]. <br> | + | <table><tr><td colspan='2'>[[4cy2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CY2 FirstGlance]. <br> |
| - | </td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cy1|4cy1]], [[4cy3|4cy3]], [[4cy5|4cy5]]</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]] 2Å</td></tr> |
| - | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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=4cy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cy2 OCA], [https://pdbe.org/4cy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cy2 RCSB], [https://www.ebi.ac.uk/pdbsum/4cy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cy2 ProSAT]</span></td></tr> |
| - | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cy2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cy2 RCSB], [http://www.ebi.ac.uk/pdbsum/4cy2 PDBsum]</span></td></tr>
| + | </table> |
| - | <table> | + | |
| - | == Disease ==
| + | |
| - | [[http://www.uniprot.org/uniprot/KANL1_HUMAN KANL1_HUMAN]] 17q21.31 microdeletion syndrome;Koolen-De Vries syndrome due to a point mutation.
| + | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN]] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref> [[http://www.uniprot.org/uniprot/KANL1_HUMAN KANL1_HUMAN]] As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription.<ref>PMID:20018852</ref> <ref>PMID:22547026</ref> [[http://www.uniprot.org/uniprot/KANL2_HUMAN KANL2_HUMAN]] As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription.<ref>PMID:20018852</ref> | + | [https://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex.,Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A Genes Dev. 2014 May 1;28(9):929-42. doi: 10.1101/gad.240200.114. PMID:24788516<ref>PMID:24788516</ref> | | Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex.,Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A Genes Dev. 2014 May 1;28(9):929-42. doi: 10.1101/gad.240200.114. PMID:24788516<ref>PMID:24788516</ref> |
| | | | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4cy2" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Brettschneider, J.]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cusack, S.]] | + | [[Category: Large Structures]] |
| - | [[Category: Dias, J.]] | + | [[Category: Brettschneider J]] |
| - | [[Category: Kadlec, J.]] | + | [[Category: Cusack S]] |
| - | [[Category: Chromatin]] | + | [[Category: Dias J]] |
| - | [[Category: Epigenetic regulator]] | + | [[Category: Kadlec J]] |
| - | [[Category: Histone acetylation]]
| + | |
| - | [[Category: Transcription]]
| + | |
| Structural highlights
Function
WDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The subunits of the nonspecific lethal (NSL) complex, which include the histone acetyltransferase MOF (males absent on the first), play important roles in various cellular functions, including transcription regulation and stem cell identity maintenance and reprogramming, and are frequently misregulated in disease. Here, we provide the first biochemical and structural insights into the molecular architecture of this large multiprotein assembly. We identified several direct interactions within the complex and show that KANSL1 acts as a scaffold protein interacting with four other subunits, including WDR5, which in turn binds KANSL2. Structural analysis of the KANSL1/WDR5/KANSL2 subcomplex reveals how WDR5 is recruited into the NSL complex via conserved linear motifs of KANSL1 and KANSL2. Using structure-based KANSL1 mutants in transgenic flies, we show that the KANSL1-WDR5 interaction is required for proper assembly, efficient recruitment of the NSL complex to target promoters, and fly viability. Our data clearly show that the interactions of WDR5 with the MOF-containing NSL complex and MLL/COMPASS histone methyltransferase complexes are mutually exclusive. We propose that rather than being a shared subunit, WDR5 plays an important role in assembling distinct histone-modifying complexes with different epigenetic regulatory roles.
Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex.,Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A Genes Dev. 2014 May 1;28(9):929-42. doi: 10.1101/gad.240200.114. PMID:24788516[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
- ↑ Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, Wu J, Lill JR, Zha J. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2009 Mar;29(5):1176-88. doi: 10.1128/MCB.01599-08. Epub 2008 Dec, 22. PMID:19103755 doi:10.1128/MCB.01599-08
- ↑ Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J Biol Chem. 2010 Feb 12;285(7):4268-72. doi: 10.1074/jbc.C109.087981. Epub 2009 , Dec 14. PMID:20018852 doi:10.1074/jbc.C109.087981
- ↑ Han Z, Guo L, Wang H, Shen Y, Deng XW, Chai J. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol Cell. 2006 Apr 7;22(1):137-44. PMID:16600877 doi:10.1016/j.molcel.2006.03.018
- ↑ Couture JF, Collazo E, Trievel RC. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 2006 Aug;13(8):698-703. Epub 2006 Jul 9. PMID:16829960 doi:10.1038/nsmb1116
- ↑ Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A. Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes Dev. 2014 May 1;28(9):929-42. doi: 10.1101/gad.240200.114. PMID:24788516 doi:http://dx.doi.org/10.1101/gad.240200.114
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