8yd8: Difference between revisions
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==Structure of FADD/Caspase-8/cFLIP death effector domain assembly== | |||
<StructureSection load='8yd8' size='340' side='right'caption='[[8yd8]], [[Resolution|resolution]] 3.11Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8yd8]] is a 10 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=8YD8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YD8 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]] 3.11Å</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=8yd8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yd8 OCA], [https://pdbe.org/8yd8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yd8 RCSB], [https://www.ebi.ac.uk/pdbsum/8yd8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yd8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CFLAR_HUMAN CFLAR_HUMAN] Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity.<ref>PMID:9880531</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease. | |||
Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.,Yang CY, Lien CI, Tseng YC, Tu YF, Kulczyk AW, Lu YC, Wang YT, Su TW, Hsu LC, Lo YC, Lin SC Nat Commun. 2024 May 6;15(1):3791. doi: 10.1038/s41467-024-47990-2. PMID:38710704<ref>PMID:38710704</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8yd8" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Lin S-C]] | |||
[[Category: Yang C-Y]] | |||
Latest revision as of 08:27, 15 May 2024
Structure of FADD/Caspase-8/cFLIP death effector domain assemblyStructure of FADD/Caspase-8/cFLIP death effector domain assembly
Structural highlights
FunctionCFLAR_HUMAN Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity.[1] Publication Abstract from PubMedFas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease. Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.,Yang CY, Lien CI, Tseng YC, Tu YF, Kulczyk AW, Lu YC, Wang YT, Su TW, Hsu LC, Lo YC, Lin SC Nat Commun. 2024 May 6;15(1):3791. doi: 10.1038/s41467-024-47990-2. PMID:38710704[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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