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| | ==Crystal Structure of the CSL-Notch-Mastermind ternary complex bound to DNA== | | ==Crystal Structure of the CSL-Notch-Mastermind ternary complex bound to DNA== |
| - | <StructureSection load='2fo1' size='340' side='right' caption='[[2fo1]], [[Resolution|resolution]] 3.12Å' scene=''> | + | <StructureSection load='2fo1' size='340' side='right'caption='[[2fo1]], [[Resolution|resolution]] 3.12Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2fo1]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Caeel Caeel]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FO1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FO1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2fo1]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Caenorhabditis_elegans Caenorhabditis elegans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FO1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FO1 FirstGlance]. <br> |
| - | </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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.12Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LAG-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6239 CAEEL]), sel-8, lag-3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6239 CAEEL]), lin-12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6239 CAEEL])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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=2fo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fo1 OCA], [http://pdbe.org/2fo1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2fo1 RCSB], [http://www.ebi.ac.uk/pdbsum/2fo1 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=2fo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fo1 OCA], [https://pdbe.org/2fo1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fo1 RCSB], [https://www.ebi.ac.uk/pdbsum/2fo1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fo1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LAG3_CAEEL LAG3_CAEEL]] Glp-1 and lin-12 promote signalling by recruiting lag-3 to target promoters, where it functions as a transcriptional activator. [[http://www.uniprot.org/uniprot/LIN12_CAEEL LIN12_CAEEL]] Involved in several cell fate decisions that require cell-cell interactions. It is possible that lin-12 encodes a membrane-bound receptor for a signal that enables expression of the ventral uterine precursor cell fate. Activity in cell fate decisions and tumorigenesis is negatively regulated by sel-10.<ref>PMID:3419531</ref> <ref>PMID:3000611</ref> | + | [https://www.uniprot.org/uniprot/LAG1_CAEEL LAG1_CAEEL] Transcriptional regulator that plays a central role in lin-12/Notch and glp-1/Notch signaling pathways, involved in cell-cell communication that regulate a broad spectrum of cell-fate determinations (PubMed:8625826). Binds directly to the 5'-[A/G]TGGGAA-3' DNA consensus sequence, which is present in the regulatory region of several genes (PubMed:15297877, PubMed:18706403, PubMed:21737278, PubMed:23615264, PubMed:32196486, PubMed:8625826). Acts as a transcriptional repressor when it is not associated with Notch proteins (By similarity). When in a complex with a Notch intracellular domain (NICD) product of lin-12/Notch or glp-1/Notch, and transcription regulator lag-3, it may act as a transcriptional activator that activates transcription of target genes (PubMed:10830967, PubMed:18381292, PubMed:32196486, PubMed:9003776). Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively (By similarity). Autonomously required in the germline for the stem cell fate, acting in the glp-1-dependent transcriptional activation of genes, including lst-1 and sygl-1 (PubMed:32196486). Involved in cell-fate specification during reproductive system development, by positively autoregulating its own expression, in response to lin-12/Notch signaling (PubMed:23615264, PubMed:32839181). Plays a role in Notch-dependent induction of left-right asymmetry in interneurons and motoneurons (PubMed:21737278). May repress expression of hlh-6, in a lin-12/Notch-independent manner (PubMed:18706403).[UniProtKB:P28159]<ref>PMID:10830967</ref> <ref>PMID:15297877</ref> <ref>PMID:18381292</ref> <ref>PMID:18706403</ref> <ref>PMID:21737278</ref> <ref>PMID:23615264</ref> <ref>PMID:32196486</ref> <ref>PMID:32839181</ref> <ref>PMID:8625826</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/fo/2fo1_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fo/2fo1_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> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2fo1 ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caeel]] | + | [[Category: Caenorhabditis elegans]] |
| - | [[Category: Kovall, R A]] | + | [[Category: Large Structures]] |
| - | [[Category: Wilson, J J]] | + | [[Category: Kovall RA]] |
| - | [[Category: Ankyrin repeat]] | + | [[Category: Wilson JJ]] |
| - | [[Category: Beta-barrel]]
| + | |
| - | [[Category: Double helix]]
| + | |
| - | [[Category: Gene regulation-signalling protein-dna complex]]
| + | |
| - | [[Category: Protein-dna complex]]
| + | |
| Structural highlights
Function
LAG1_CAEEL Transcriptional regulator that plays a central role in lin-12/Notch and glp-1/Notch signaling pathways, involved in cell-cell communication that regulate a broad spectrum of cell-fate determinations (PubMed:8625826). Binds directly to the 5'-[A/G]TGGGAA-3' DNA consensus sequence, which is present in the regulatory region of several genes (PubMed:15297877, PubMed:18706403, PubMed:21737278, PubMed:23615264, PubMed:32196486, PubMed:8625826). Acts as a transcriptional repressor when it is not associated with Notch proteins (By similarity). When in a complex with a Notch intracellular domain (NICD) product of lin-12/Notch or glp-1/Notch, and transcription regulator lag-3, it may act as a transcriptional activator that activates transcription of target genes (PubMed:10830967, PubMed:18381292, PubMed:32196486, PubMed:9003776). Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively (By similarity). Autonomously required in the germline for the stem cell fate, acting in the glp-1-dependent transcriptional activation of genes, including lst-1 and sygl-1 (PubMed:32196486). Involved in cell-fate specification during reproductive system development, by positively autoregulating its own expression, in response to lin-12/Notch signaling (PubMed:23615264, PubMed:32839181). Plays a role in Notch-dependent induction of left-right asymmetry in interneurons and motoneurons (PubMed:21737278). May repress expression of hlh-6, in a lin-12/Notch-independent manner (PubMed:18706403).[UniProtKB:P28159][1] [2] [3] [4] [5] [6] [7] [8] [9]
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
Notch signaling mediates communication between cells and is essential for proper embryonic patterning and development. CSL is a DNA binding transcription factor that regulates transcription of Notch target genes by interacting with coregulators. Transcriptional activation requires the displacement of corepressors from CSL by the intracellular portion of the receptor Notch (NotchIC) and the recruitment of the coactivator protein Mastermind to the complex. Here we report the 3.1 A structure of the ternary complex formed by CSL, NotchIC, and Mastermind bound to DNA. As expected, the RAM domain of Notch interacts with the beta trefoil domain of CSL; however, the C-terminal domain of CSL has an unanticipated central role in the interface formed with the Notch ankyrin repeats and Mastermind. Ternary complex formation induces a substantial conformational change within CSL, suggesting a molecular mechanism for the conversion of CSL from a repressor to an activator.
Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA.,Wilson JJ, Kovall RA Cell. 2006 Mar 10;124(5):985-96. PMID:16530045[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Petcherski AG, Kimble J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature. 2000 May 18;405(6784):364-8. PMID:10830967 doi:10.1038/35012645
- ↑ Kovall RA, Hendrickson WA. Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. EMBO J. 2004 Sep 1;23(17):3441-51. Epub 2004 Aug 5. PMID:15297877 doi:10.1038/sj.emboj.7600349
- ↑ Friedmann DR, Wilson JJ, Kovall RA. RAM-induced allostery facilitates assembly of a notch pathway active transcription complex. J Biol Chem. 2008 May 23;283(21):14781-91. Epub 2008 Apr 1. PMID:18381292 doi:http://dx.doi.org/10.1074/jbc.M709501200
- ↑ Ghai V, Gaudet J. The CSL transcription factor LAG-1 directly represses hlh-6 expression in C. elegans. Dev Biol. 2008 Oct 15;322(2):334-44. PMID:18706403 doi:10.1016/j.ydbio.2008.07.018
- ↑ Bertrand V, Bisso P, Poole RJ, Hobert O. Notch-dependent induction of left/right asymmetry in C. elegans interneurons and motoneurons. Curr Biol. 2011 Jul 26;21(14):1225-31. PMID:21737278 doi:10.1016/j.cub.2011.06.016
- ↑ Choi VN, Park SK, Hwang BJ. Clustered LAG-1 binding sites in lag-1/CSL are involved in regulating lag-1 expression during lin-12/Notch-dependent cell-fate specification. BMB Rep. 2013 Apr;46(4):219-24. PMID:23615264 doi:10.5483/bmbrep.2013.46.4.269
- ↑ Chen J, Mohammad A, Pazdernik N, Huang H, Bowman B, Tycksen E, Schedl T. GLP-1 Notch-LAG-1 CSL control of the germline stem cell fate is mediated by transcriptional targets lst-1 and sygl-1. PLoS Genet. 2020 Mar 20;16(3):e1008650. PMID:32196486 doi:10.1371/journal.pgen.1008650
- ↑ Luo KL, Underwood RS, Greenwald I. Positive autoregulation of lag-1 in response to LIN-12 activation in cell fate decisions during C. elegans reproductive system development. Development. 2020 Sep 28;147(18):dev193482. PMID:32839181 doi:10.1242/dev.193482
- ↑ Christensen S, Kodoyianni V, Bosenberg M, Friedman L, Kimble J. lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development. 1996 May;122(5):1373-83. PMID:8625826 doi:10.1242/dev.122.5.1373
- ↑ Wilson JJ, Kovall RA. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell. 2006 Mar 10;124(5):985-96. PMID:16530045 doi:10.1016/j.cell.2006.01.035
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