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| | ==Crystal structure of the 3-MBT domain from human L3MBTL1 in complex with p53K382me1== | | ==Crystal structure of the 3-MBT domain from human L3MBTL1 in complex with p53K382me1== |
| - | <StructureSection load='3oq5' size='340' side='right' caption='[[3oq5]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='3oq5' size='340' side='right'caption='[[3oq5]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3oq5]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OQ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OQ5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3oq5]] is a 5 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=3OQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OQ5 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</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]] 2.5005Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">L3MBTL, KIAA0681, L3MBT, L3MBTL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</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=3oq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oq5 OCA], [http://pdbe.org/3oq5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3oq5 RCSB], [http://www.ebi.ac.uk/pdbsum/3oq5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3oq5 ProSAT]</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=3oq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oq5 OCA], [https://pdbe.org/3oq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oq5 RCSB], [https://www.ebi.ac.uk/pdbsum/3oq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oq5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LMBL1_HUMAN LMBL1_HUMAN]] Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post-translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.<ref>PMID:17540172</ref> <ref>PMID:18408754</ref> <ref>PMID:20870719</ref> <ref>PMID:20870725</ref> [[http://www.uniprot.org/uniprot/Q5U0E4_HUMAN Q5U0E4_HUMAN]] Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression (By similarity).[RuleBase:RU003304] | + | [https://www.uniprot.org/uniprot/LMBL1_HUMAN LMBL1_HUMAN] Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post-translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.<ref>PMID:17540172</ref> <ref>PMID:18408754</ref> <ref>PMID:20870719</ref> <ref>PMID:20870725</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/oq/3oq5_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/oq/3oq5_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: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Appella, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Gozani, O]] | + | [[Category: Appella E]] |
| - | [[Category: Hayashi, R]] | + | [[Category: Gozani O]] |
| - | [[Category: Kutateladze, T]] | + | [[Category: Hayashi R]] |
| - | [[Category: Roy, S]] | + | [[Category: Kutateladze T]] |
| - | [[Category: Shi, X]] | + | [[Category: Roy S]] |
| - | [[Category: Weiner, K L]] | + | [[Category: Shi X]] |
| - | [[Category: West, L E]] | + | [[Category: Weiner KL]] |
| - | [[Category: Chromatin regulator]]
| + | [[Category: West LE]] |
| - | [[Category: Chromosomal protein]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Malignant brain tumor]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Methylation]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: P53]]
| + | |
| - | [[Category: Protein lysine methyltransferase]]
| + | |
| - | [[Category: Repressor]]
| + | |
| - | [[Category: Three-leaved beta-propeller]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Function
LMBL1_HUMAN Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post-translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.[1] [2] [3] [4]
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 p53 tumor suppressor protein is regulated by multiple post-translational modifications, including lysine methylation. We previously found that monomethylation of p53 at lysine 382 (p53K382me1) by the protein lysine methyltransferase (PKMT) SET8/PR-Set7 represses p53 transactivation of target genes. However, the molecular mechanism linking p53K382 monomethylation to repression is not known. Here we show in biochemical and crystallographic studies the preferential recognition of p53K382me1 by the triple malignant brain tumor (MBT)-repeats of the chromatin compaction factor L3MBTL1. We demonstrate that SET8-mediated methylation of p53 at K382 promotes the interaction between L3MBTL1 and p53 in cells, and the chromatin occupancy of L3MBTL1 at p53 target promoters. In the absence of DNA damage, L3MBTL1 interacts with p53K382me1 and p53-target genes are repressed, whereas depletion of L3MBTL1 results in a p53-dependent increase in p21 and PUMA transcript levels. Activation of p53 by DNA damage is coupled to a decrease in p53K382me1 levels, abrogation of the L3MBTL1-p53 interaction, and disassociation of L3MBTL1 from p53-target promoters. Together, we identify L3MBTL1 as the second known methyl-p53 effector protein, and provide a molecular explanation for the mechanism by which p53K382me1 is transduced to regulate p53 activity.
The MBT repeats of L3MBTL1 link set8 mediated p53 methylation at lysine 382 to target gene repression.,West LE, Roy S, Lachmi-Weiner K, Hayashi R, Shi X, Appella E, Kutateladze TG, Gozani O J Biol Chem. 2010 Sep 24. PMID:20870725[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Trojer P, Li G, Sims RJ 3rd, Vaquero A, Kalakonda N, Boccuni P, Lee D, Erdjument-Bromage H, Tempst P, Nimer SD, Wang YH, Reinberg D. L3MBTL1, a histone-methylation-dependent chromatin lock. Cell. 2007 Jun 1;129(5):915-28. PMID:17540172 doi:10.1016/j.cell.2007.03.048
- ↑ Kalakonda N, Fischle W, Boccuni P, Gurvich N, Hoya-Arias R, Zhao X, Miyata Y, Macgrogan D, Zhang J, Sims JK, Rice JC, Nimer SD. Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1. Oncogene. 2008 Jul 17;27(31):4293-304. doi: 10.1038/onc.2008.67. Epub 2008 Apr, 14. PMID:18408754 doi:10.1038/onc.2008.67
- ↑ Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem. 2010 Nov 26;285(48):37733-40. doi: 10.1074/jbc.M110.137612. Epub, 2010 Sep 24. PMID:20870719 doi:10.1074/jbc.M110.137612
- ↑ West LE, Roy S, Lachmi-Weiner K, Hayashi R, Shi X, Appella E, Kutateladze TG, Gozani O. The MBT repeats of L3MBTL1 link set8 mediated p53 methylation at lysine 382 to target gene repression. J Biol Chem. 2010 Sep 24. PMID:20870725 doi:10.1074/jbc.M110.139527
- ↑ West LE, Roy S, Lachmi-Weiner K, Hayashi R, Shi X, Appella E, Kutateladze TG, Gozani O. The MBT repeats of L3MBTL1 link set8 mediated p53 methylation at lysine 382 to target gene repression. J Biol Chem. 2010 Sep 24. PMID:20870725 doi:10.1074/jbc.M110.139527
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