1f9e

From Proteopedia

(Difference between revisions)

Revision as of 22:54, 22 December 2014

CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO

Structural highlights

1f9e is a 18 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	,
Related:	1qdu, 1qtn, 1pau, 1cp3
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[CASP8_HUMAN] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.^[1]

Function

[CASP8_HUMAN] Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.^[2] ^[3]

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

Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor.

Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex.,Blanchard H, Donepudi M, Tschopp M, Kodandapani L, Wu JC, Grutter MG J Mol Biol. 2000 Sep 8;302(1):9-16. PMID:10964557^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 Sep 26;419(6905):395-9. PMID:12353035 doi:10.1038/nature01063
↑ Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood. 2002 Jun 1;99(11):4070-8. PMID:12010809
↑ Muzio M, Salvesen GS, Dixit VM. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem. 1997 Jan 31;272(5):2952-6. PMID:9006941
↑ Blanchard H, Donepudi M, Tschopp M, Kodandapani L, Wu JC, Grutter MG. Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex. J Mol Biol. 2000 Sep 8;302(1):9-16. PMID:10964557 doi:10.1006/jmbi.2000.4041

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1f9e"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1f9e]] is a 18 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F9E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1F9E FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ASA:ASPARTIC+ALDEHYDE'>ASA</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr>
+</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ASA:ASPARTIC+ALDEHYDE'>ASA</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qdu|1qdu]], [[1qtn|1qtn]], [[1pau|1pau]], [[1cp3|1cp3]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qdu|1qdu]], [[1qtn|1qtn]], [[1pau|1pau]], [[1cp3|1cp3]]</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1f9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f9e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1f9e RCSB], [http://www.ebi.ac.uk/pdbsum/1f9e PDBsum]</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=1f9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f9e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1f9e RCSB], [http://www.ebi.ac.uk/pdbsum/1f9e PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN]] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:[http://omim.org/entry/607271 607271]]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.<ref>PMID:12353035</ref>
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Blanchard, H.]]
+[[Category: Blanchard, H]]
-[[Category: Donepudi, M.]]
+[[Category: Donepudi, M]]
-[[Category: Grutter, M G.]]
+[[Category: Grutter, M G]]
-[[Category: Kodandapani, L.]]
+[[Category: Kodandapani, L]]
-[[Category: Tschopp, M.]]
+[[Category: Tschopp, M]]
-[[Category: Wu, J C.]]
+[[Category: Wu, J C]]
 [[Category: Apoptosis]]
 [[Category: Caspase-8]]

1f9e

From Proteopedia

Revision as of 22:54, 22 December 2014

CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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