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| | ==Crystal structure of Apaf-1 CARD and caspase-9 CARD complex== | | ==Crystal structure of Apaf-1 CARD and caspase-9 CARD complex== |
| - | <StructureSection load='4rhw' size='340' side='right' caption='[[4rhw]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4rhw' size='340' side='right'caption='[[4rhw]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rhw]] is a 6 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=4RHW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RHW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rhw]] is a 6 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=4RHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RHW 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=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </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=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APAF1, KIAA0413 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CASP9, MCH6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4rhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhw OCA], [https://pdbe.org/4rhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rhw RCSB], [https://www.ebi.ac.uk/pdbsum/4rhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rhw ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-9 Caspase-9], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.62 3.4.22.62] </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=4rhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhw OCA], [http://pdbe.org/4rhw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rhw RCSB], [http://www.ebi.ac.uk/pdbsum/4rhw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rhw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/APAF_HUMAN APAF_HUMAN]] Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.<ref>PMID:10393175</ref> <ref>PMID:12804598</ref> [[http://www.uniprot.org/uniprot/CASP9_HUMAN CASP9_HUMAN]] Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).<ref>PMID:15657060</ref> Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.<ref>PMID:15657060</ref> | + | [https://www.uniprot.org/uniprot/APAF_HUMAN APAF_HUMAN] Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.<ref>PMID:10393175</ref> <ref>PMID:12804598</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Apoptotic protease-activating factor|Apoptotic protease-activating factor]] | + | *[[Apoptotic protease-activating factor-1 3D structures|Apoptotic protease-activating factor-1 3D structures]] |
| - | *[[Caspase|Caspase]] | + | *[[Caspase 3D structures|Caspase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caspase-9]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Hu, Q]] | + | [[Category: Hu Q]] |
| - | [[Category: Shi, Y]] | + | [[Category: Shi Y]] |
| - | [[Category: Wu, D]] | + | [[Category: Wu D]] |
| - | [[Category: Yan, C]] | + | [[Category: Yan C]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Death domain superfamily]]
| + | |
| Structural highlights
Function
APAF_HUMAN Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.[1] [2]
Publication Abstract from PubMed
Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrate that the previously reported 1:1 interaction between Apaf-1 caspase recruitment domain (CARD) and caspase-9 CARD is insufficient for the activation of caspase-9. Rather, formation of a multimeric CARD:CARD assembly between Apaf-1 and caspase-9, which requires three types of distinct interfaces, underlies caspase-9 activation. Importantly, an additional surface area on the multimeric CARD assembly is essential for caspase-9 activation. Together, these findings reveal mechanistic insights into the activation of caspase-9 by the Apaf-1 apoptosome and support the induced conformation model for initiator caspase activation by adaptor complexes.
Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.,Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q, Shi Y Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16254-61. doi:, 10.1073/pnas.1418000111. Epub 2014 Oct 13. PMID:25313070[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hu Y, Benedict MA, Ding L, Nunez G. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 1999 Jul 1;18(13):3586-95. PMID:10393175 doi:10.1093/emboj/18.13.3586
- ↑ Ogawa T, Shiga K, Hashimoto S, Kobayashi T, Horii A, Furukawa T. APAF-1-ALT, a novel alternative splicing form of APAF-1, potentially causes impeded ability of undergoing DNA damage-induced apoptosis in the LNCaP human prostate cancer cell line. Biochem Biophys Res Commun. 2003 Jun 27;306(2):537-43. PMID:12804598
- ↑ Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q, Shi Y. Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome. Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16254-61. doi:, 10.1073/pnas.1418000111. Epub 2014 Oct 13. PMID:25313070 doi:http://dx.doi.org/10.1073/pnas.1418000111
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