1i4e

<table><tr><td colspan='2'>[[1i4e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Acmnpv Acmnpv] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I4E OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1I4E FirstGlance]. <br>

</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>

<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">P35 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=46015 AcMNPV]), CASP8, MCH5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-8 Caspase-8], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.61 3.4.22.61] </span></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i4e OCA], [http://pdbe.org/1i4e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1i4e RCSB], [http://www.ebi.ac.uk/pdbsum/1i4e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1i4e ProSAT]</span></td></tr>

== 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>

[[http://www.uniprot.org/uniprot/VP35_NPVAC VP35_NPVAC]] Blocks the insect or worm host cells apoptotic response initiated by the viral infection. Confers protection from cell death in mammalian cells. Acts by blocking the activity of members of the caspase family of proteases. Required for late and very late gene expression. [[http://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 ==

Apoptosis is a highly regulated process that is crucial for normal development and homeostasis of multicellular organisms. The p35 protein from baculoviruses effectively prevents apoptosis by its broad-spectrum caspase inhibition. Here we report the crystal structure of p35 in complex with human caspase-8 at 3.0 A resolution, and biochemical and mutagenesis studies based on the structural information. The structure reveals that the caspase is inhibited in the active site through a covalent thioester linkage to p35, which we confirmed by gel electrophoresis, hydroxylamine treatment and mass spectrometry experiments. The p35 protein undergoes dramatic conformational changes on cleavage by the caspase. The repositioning of the amino terminus of p35 into the active site of the caspase eliminates solvent accessibility of the catalytic dyad. This may be crucial for preventing hydrolysis of the thioester intermediate, which is supported by the abrogation of inhibitory activity through mutations at the N terminus of p35. The p35 protein also makes conserved contacts with the caspase outside the active-site region, providing the molecular basis for the broad-spectrum inhibitory activity of this protein. We demonstrate a new molecular mechanism of caspase inhibition, as well as protease inhibition in general.

Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex.,Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H Nature. 2001 Mar 22;410(6827):494-7. PMID:11260720<ref>PMID:11260720</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

</div>

<div class="pdbe-citations 1i4e" style="background-color:#fffaf0;"></div>

*[[User:Christopher French|User:Christopher French]]

[[Category: Acmnpv]]

[[Category: Caspase-8]]

[[Category: Human]]

[[Category: Cirilli, M]]

[[Category: Huang, Y]]

[[Category: Myszka, D G]]

[[Category: Rich, R L]]

[[Category: Wu, H]]

[[Category: Xu, G]]

[[Category: Covalent complex protease-inhibitor]]