1nw9: Difference between revisions

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-[[Image:1nw9.gif|left|200px]]<br /><applet load="1nw9" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="1nw9, resolution 2.40&Aring;" />
-'''STRUCTURE OF CASPASE-9 IN AN INHIBITORY COMPLEX WITH XIAP-BIR3'''<br />
-==Overview==
+==STRUCTURE OF CASPASE-9 IN AN INHIBITORY COMPLEX WITH XIAP-BIR3==
-The inhibitor of apoptosis (IAP) proteins potently inhibit the catalytic activity of caspases. While profound insight into the inhibition of the effector caspases has been gained in recent years, the mechanism of how the initiator caspase-9 is regulated by IAPs remains enigmatic. This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral IAP repeat (BIR3) of XIAP at 2.4 A resolution. The structure reveals that the BIR3 domain forms a heterodimer with a caspase-9 monomer. Strikingly, the surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. We demonstrate that monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. Thus, XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. These studies, in conjunction with other observations, define a unified mechanism for the activation of all caspases.
+<StructureSection load='1nw9' size='340' side='right'caption='[[1nw9]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1nw9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The August 2004 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Caspases''  by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2004_8 10.2210/rcsb_pdb/mom_2004_8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NW9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NW9 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=1nw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nw9 OCA], [https://pdbe.org/1nw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nw9 RCSB], [https://www.ebi.ac.uk/pdbsum/1nw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nw9 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[https://omim.org/entry/300635 300635]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nw/1nw9_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </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/main_output.php?pdb_ID=1nw9 ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known diseases associated with this structure: Lymphoproliferative syndrome, X-linked, 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300079 300079]]
+*[[Caspase 3D structures|Caspase 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-NW9 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. The following page contains interesting information on the relation of 1NW9 with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb56_1.html Caspases]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NW9 OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Mechanism of XIAP-mediated inhibition of caspase-9., Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y, Mol Cell. 2003 Feb;11(2):519-27. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12620238 12620238]
 [[Category: Caspases]]
 [[Category: Homo sapiens]]
-[[Category: Protein complex]]
+[[Category: Large Structures]]
-[[Category: Alnemri, E S.]]
+[[Category: RCSB PDB Molecule of the Month]]
-[[Category: Chai, J.]]
+[[Category: Alnemri ES]]
-[[Category: Fairman, R.]]
+[[Category: Chai J]]
-[[Category: Li, P.]]
+[[Category: Fairman R]]
-[[Category: Riedl, S J.]]
+[[Category: Li P]]
-[[Category: Rigotti, D J.]]
+[[Category: Riedl SJ]]
-[[Category: Shi, Y.]]
+[[Category: Rigotti DJ]]
-[[Category: Shiozaki, E N.]]
+[[Category: Shi Y]]
-[[Category: Srinivasula, S M.]]
+[[Category: Shiozaki EN]]
-[[Category: ZN]]
+[[Category: Srinivasula SM]]
-[[Category: apoptosis]]
-[[Category: caspase activation]]
-[[Category: caspase inhibition]]
-[[Category: caspase-9]]
-[[Category: dimerization]]
-[[Category: xiap]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:10:46 2008''