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<StructureSection load='7lvm' size='340' side='right'caption='[[7lvm]], [[Resolution|resolution]] 1.47&Aring;' scene=''>
<StructureSection load='7lvm' size='340' side='right'caption='[[7lvm]], [[Resolution|resolution]] 1.47&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7lvm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LVM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LVM FirstGlance]. <br>
<table><tr><td colspan='2'>[[7lvm]] is a 1 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=7LVM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LVM FirstGlance]. <br>
</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=7lvm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lvm OCA], [https://pdbe.org/7lvm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lvm RCSB], [https://www.ebi.ac.uk/pdbsum/7lvm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lvm ProSAT]</span></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]] 1.47&#8491;</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=7lvm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lvm OCA], [https://pdbe.org/7lvm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lvm RCSB], [https://www.ebi.ac.uk/pdbsum/7lvm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lvm ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[https://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN]] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:[https://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>
[https://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:[https://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>  
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/CASP8_HUMAN 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.<ref>PMID:12010809</ref> <ref>PMID:9006941</ref>
[https://www.uniprot.org/uniprot/CASP8_HUMAN 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.<ref>PMID:12010809</ref> <ref>PMID:9006941</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase-8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs. METHODS: RA FLS lines were obtained from synovial tissues at arthroplasty and used at passage 5-8. Caspase-8 was silenced using small interfering RNA, and its effect was determined in cell adhesion, migration and invasion assays. Quantitative reverse transcription PCR and western blot were used to assess gene and protein expression, respectively. A caspase-8 selective inhibitor was used determine the role of enzymatic activity on FLS migration and invasion. Caspase-8 isoform transcripts and epigenetic marks in FLSs were analyzed in FLS public databases. Crystal structures of caspase-8B and G were determined. RESULTS: Caspase-8 deficiency in RA FLSs reduced cell adhesion, migration, and invasion independent of its catalytic activity. Epigenetic and transcriptomic analyses of RA FLSs revealed that a specific caspase-8 isoform, variant G, is the dominant isoform expressed (~80% of total caspase-8) and induced by PDGF. The crystal structures of caspase-8 variant G and B were identical except for a unique unstructured 59 amino acid N-terminal domain in variant G. Selective knockdown of caspase-8G was solely responsible for the effects of caspase-8 on calpain activity and cell invasion in FLS. CONCLUSION: Blocking caspase-8 variant G could decrease cell invasion in diseases like RA without the potential deleterious effects of nonspecific caspase-8 inhibition.


Caspase-8 Variant G Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Aggressive Behavior.,Ansalone C, Ainsworth RI, Nygaard G, Ai R, Prideaux EB, Hammaker D, Perumal NB, Weichert K, Tung F, Kodandapani L, Sauder JM, Mertsching EC, Benschop RJ, Boyle DL, Wang W, Firestein GS ACR Open Rheumatol. 2021 Dec 28. doi: 10.1002/acr2.11384. PMID:34963199<ref>PMID:34963199</ref>
==See Also==
 
*[[Caspase 3D structures|Caspase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lvm" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Kodandapani, L]]
[[Category: Kodandapani L]]
[[Category: Lu, F]]
[[Category: Lu F]]
[[Category: Sauder, J M]]
[[Category: Sauder JM]]
[[Category: Weichert, K]]
[[Category: Weichert K]]
[[Category: Casp8]]
[[Category: Casp8b ded]]
[[Category: Gene id: 841]]
[[Category: Hydrolase]]

Latest revision as of 10:18, 3 April 2024

CASP8 isoform B DED domainCASP8 isoform B DED domain

Structural highlights

7lvm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.47Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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

7lvm, resolution 1.47Å

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