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| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[2ar9]] is a 4 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=2AR9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AR9 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[2ar9]] is a 4 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=2AR9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AR9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLT:D-MALATE'>MLT</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]] 2.8Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLT:D-MALATE'>MLT</scene></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=2ar9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ar9 OCA], [https://pdbe.org/2ar9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ar9 RCSB], [https://www.ebi.ac.uk/pdbsum/2ar9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ar9 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=2ar9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ar9 OCA], [https://pdbe.org/2ar9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ar9 RCSB], [https://www.ebi.ac.uk/pdbsum/2ar9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ar9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://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/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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chao, Y]] | + | [[Category: Chao Y]] |
| - | [[Category: Fairman, R]] | + | [[Category: Fairman R]] |
| - | [[Category: Rigotti, D J]] | + | [[Category: Rigotti DJ]] |
| - | [[Category: Shi, Y]] | + | [[Category: Shi Y]] |
| - | [[Category: Shiozaki, E N]] | + | [[Category: Shiozaki EN]] |
| - | [[Category: Srinivassula, S M]] | + | [[Category: Srinivassula SM]] |
| - | [[Category: Caspase]]
| + | |
| - | [[Category: Caspase activation]]
| + | |
| - | [[Category: Cysteine protease]]
| + | |
| - | [[Category: Engineered caspase-9]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Initiator caspase]]
| + | |
| Structural highlights
Function
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).[1] Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.[2]
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
Caspases are responsible for the execution of programmed cell death (apoptosis) and must undergo proteolytic activation, in response to apoptotic stimuli, to function. The mechanism of initiator caspase activation has been generalized by the induced proximity model, which is thought to drive dimerization-mediated activation of caspases. The initiator caspase, caspase-9, exists predominantly as a monomer in solution. To examine the induced proximity model, we engineered a constitutively dimeric caspase-9 by relieving steric hindrance at the dimer interface. Crystal structure of the engineered caspase-9 closely resembles that of the wild-type (WT) caspase-9, including all relevant structural details and the asymmetric nature of two monomers. Compared to the WT caspase-9, this engineered dimer exhibits a higher level of catalytic activity in vitro and induces more efficient cell death when expressed. However, the catalytic activity of the dimeric caspase-9 is only a small fraction of that for the Apaf-1-activated caspase-9. Furthermore, in contrast to the WT caspase-9, the activity of the dimeric caspase-9 can no longer be significantly enhanced in an Apaf-1-dependent manner. These findings suggest that dimerization of caspase-9 may be qualitatively different from its activation by Apaf-1, and in conjunction with other evidence, posit an induced conformation model for the activation of initiator caspases.
Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation.,Chao Y, Shiozaki EN, Srinivasula SM, Rigotti DJ, Fairman R, Shi Y PLoS Biol. 2005 Jun;3(6):e183. Epub 2005 May 10. PMID:15941357[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D. c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem. 2005 Mar 25;280(12):11147-51. Epub 2005 Jan 18. PMID:15657060 doi:10.1074/jbc.M413787200
- ↑ Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D. c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem. 2005 Mar 25;280(12):11147-51. Epub 2005 Jan 18. PMID:15657060 doi:10.1074/jbc.M413787200
- ↑ Chao Y, Shiozaki EN, Srinivasula SM, Rigotti DJ, Fairman R, Shi Y. Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation. PLoS Biol. 2005 Jun;3(6):e183. Epub 2005 May 10. PMID:15941357 doi:10.1371/journal.pbio.0030183
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