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| | ==crystal structure of CED-4 bound CED-3 fragment== | | ==crystal structure of CED-4 bound CED-3 fragment== |
| - | <StructureSection load='4m9s' size='340' side='right' caption='[[4m9s]], [[Resolution|resolution]] 3.21Å' scene=''> | + | <StructureSection load='4m9s' size='340' side='right'caption='[[4m9s]], [[Resolution|resolution]] 3.21Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m9s]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Caenorhabditis_elegans Caenorhabditis elegans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M9S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M9S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m9s]] is a 8 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=4M9S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M9S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 3.207Å</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> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3lqq|3lqq]], [[4m9x|4m9x]], [[4m9y|4m9y]], [[4m9z|4m9z]]</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=4m9s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m9s OCA], [https://pdbe.org/4m9s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m9s RCSB], [https://www.ebi.ac.uk/pdbsum/4m9s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m9s ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ced-4, C35D10.9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6239 Caenorhabditis elegans])</td></tr>
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| - | <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=4m9s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m9s OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4m9s RCSB], [http://www.ebi.ac.uk/pdbsum/4m9s PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CED4_CAEEL CED4_CAEEL]] Isoform a plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3. Isoform b prevents PCD.<ref>PMID:1286611</ref> <ref>PMID:8706125</ref> <ref>PMID:9027313</ref> <ref>PMID:10688797</ref> <ref>PMID:15383288</ref> | + | [https://www.uniprot.org/uniprot/CED4_CAEEL CED4_CAEEL] Isoform a plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3. Isoform b prevents PCD.<ref>PMID:1286611</ref> <ref>PMID:8706125</ref> <ref>PMID:9027313</ref> <ref>PMID:10688797</ref> <ref>PMID:15383288</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | 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 4m9s" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Cell death protein|Cell death protein]] | + | *[[Cell death protein 3D structures|Cell death protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Caenorhabditis elegans]] | | [[Category: Caenorhabditis elegans]] |
| - | [[Category: Choi, W Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Huang, W J]] | + | [[Category: Choi WY]] |
| - | [[Category: Jinag, T Y]] | + | [[Category: Huang WJ]] |
| - | [[Category: Shi, Y G]] | + | [[Category: Jinag TY]] |
| - | [[Category: Wang, J W]] | + | [[Category: Shi YG]] |
| - | [[Category: Apoptosis]] | + | [[Category: Wang JW]] |
| - | [[Category: Apoptosome]]
| + | |
| - | [[Category: Ced-3]]
| + | |
| Structural highlights
Function
CED4_CAEEL Isoform a plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3. Isoform b prevents PCD.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4-CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 A resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4-CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.
Mechanistic insights into CED-4-mediated activation of CED-3.,Huang W, Jiang T, Choi W, Qi S, Pang Y, Hu Q, Xu Y, Gong X, Jeffrey PD, Wang J, Shi Y Genes Dev. 2013 Sep 15;27(18):2039-48. doi: 10.1101/gad.224428.113. PMID:24065769[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yuan J, Horvitz HR. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development. 1992 Oct;116(2):309-20. PMID:1286611
- ↑ Shaham S, Horvitz HR. An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell. 1996 Jul 26;86(2):201-8. PMID:8706125
- ↑ Wu D, Wallen HD, Nunez G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science. 1997 Feb 21;275(5303):1126-9. PMID:9027313
- ↑ Chen F, Hersh BM, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, Horvitz HR. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science. 2000 Feb 25;287(5457):1485-9. PMID:10688797
- ↑ Yan N, Gu L, Kokel D, Chai J, Li W, Han A, Chen L, Xue D, Shi Y. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell. 2004 Sep 24;15(6):999-1006. PMID:15383288 doi:10.1016/j.molcel.2004.08.022
- ↑ Huang W, Jiang T, Choi W, Qi S, Pang Y, Hu Q, Xu Y, Gong X, Jeffrey PD, Wang J, Shi Y. Mechanistic insights into CED-4-mediated activation of CED-3. Genes Dev. 2013 Sep 15;27(18):2039-48. doi: 10.1101/gad.224428.113. PMID:24065769 doi:http://dx.doi.org/10.1101/gad.224428.113
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