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| | ==Assembly of methylated LSD1 and CHD1 drives AR-dependent transcription and translocation== | | ==Assembly of methylated LSD1 and CHD1 drives AR-dependent transcription and translocation== |
| - | <StructureSection load='5afw' size='340' side='right' caption='[[5afw]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='5afw' size='340' side='right'caption='[[5afw]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5afw]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AFW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AFW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5afw]] is a 2 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=5AFW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AFW 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>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.6Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_helicase DNA helicase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.12 3.6.4.12] </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=5afw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5afw OCA], [https://pdbe.org/5afw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5afw RCSB], [https://www.ebi.ac.uk/pdbsum/5afw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5afw 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=5afw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5afw OCA], [http://pdbe.org/5afw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5afw RCSB], [http://www.ebi.ac.uk/pdbsum/5afw PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CHD1_HUMAN CHD1_HUMAN]] ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3. Required for maintaining open chromatin and pluripotency in embryonic stem cells.<ref>PMID:18042460</ref> [[http://www.uniprot.org/uniprot/KDM1A_HUMAN KDM1A_HUMAN]] Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12032298</ref> <ref>PMID:15620353</ref> <ref>PMID:16079795</ref> <ref>PMID:17805299</ref> <ref>PMID:20228790</ref> | + | [https://www.uniprot.org/uniprot/CHD1_HUMAN CHD1_HUMAN] ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3. Required for maintaining open chromatin and pluripotency in embryonic stem cells.<ref>PMID:18042460</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5afw" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5afw" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Chromodomain-helicase-DNA-binding protein 3D structures|Chromodomain-helicase-DNA-binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA helicase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Bedford, M T]] | + | [[Category: Large Structures]] |
| - | [[Category: Dengjel, J]] | + | [[Category: Bedford MT]] |
| - | [[Category: Eberlin, A]] | + | [[Category: Dengjel J]] |
| - | [[Category: Einsle, O]] | + | [[Category: Eberlin A]] |
| - | [[Category: Espejo, A]] | + | [[Category: Einsle O]] |
| - | [[Category: Flaig, R]] | + | [[Category: Espejo A]] |
| - | [[Category: Gerhardt, S]] | + | [[Category: Flaig R]] |
| - | [[Category: McMillan, J]] | + | [[Category: Gerhardt S]] |
| - | [[Category: Metzger, E]] | + | [[Category: McMillan J]] |
| - | [[Category: Metzger, P]] | + | [[Category: Metzger E]] |
| - | [[Category: Perner, S]] | + | [[Category: Metzger P]] |
| - | [[Category: Petroll, K]] | + | [[Category: Perner S]] |
| - | [[Category: Schleicher, M]] | + | [[Category: Petroll K]] |
| - | [[Category: Schott, A K]] | + | [[Category: Schleicher M]] |
| - | [[Category: Schuele, K M]] | + | [[Category: Schott AK]] |
| - | [[Category: Schuele, R]] | + | [[Category: Schuele KM]] |
| - | [[Category: Willmann, D]] | + | [[Category: Schuele R]] |
| - | [[Category: Wohlwend, D]] | + | [[Category: Willmann D]] |
| - | [[Category: VonMaessenhausen, A]] | + | [[Category: Wohlwend D]] |
| - | [[Category: Androgen receptor]]
| + | [[Category: VonMaessenhausen A]] |
| - | [[Category: Chd1]]
| + | |
| - | [[Category: G9a]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lsd1k114me2]]
| + | |
| - | [[Category: Prostate cancer]]
| + | |
| - | [[Category: Tmprrs2-erg]]
| + | |
| Structural highlights
Function
CHD1_HUMAN ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3. Required for maintaining open chromatin and pluripotency in embryonic stem cells.[1]
Publication Abstract from PubMed
Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution.
Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.,Metzger E, Willmann D, McMillan J, Forne I, Metzger P, Gerhardt S, Petroll K, von Maessenhausen A, Urban S, Schott AK, Espejo A, Eberlin A, Wohlwend D, Schule KM, Schleicher M, Perner S, Bedford MT, Jung M, Dengjel J, Flaig R, Imhof A, Einsle O, Schule R Nat Struct Mol Biol. 2016 Jan 11. doi: 10.1038/nsmb.3153. PMID:26751641[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sims RJ 3rd, Millhouse S, Chen CF, Lewis BA, Erdjument-Bromage H, Tempst P, Manley JL, Reinberg D. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol Cell. 2007 Nov 30;28(4):665-76. PMID:18042460 doi:http://dx.doi.org/10.1016/j.molcel.2007.11.010
- ↑ Metzger E, Willmann D, McMillan J, Forne I, Metzger P, Gerhardt S, Petroll K, von Maessenhausen A, Urban S, Schott AK, Espejo A, Eberlin A, Wohlwend D, Schule KM, Schleicher M, Perner S, Bedford MT, Jung M, Dengjel J, Flaig R, Imhof A, Einsle O, Schule R. Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Nat Struct Mol Biol. 2016 Jan 11. doi: 10.1038/nsmb.3153. PMID:26751641 doi:http://dx.doi.org/10.1038/nsmb.3153
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