6n1h
From Proteopedia
(Difference between revisions)
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<SX load='6n1h' size='340' side='right' viewer='molstar' caption='[[6n1h]], [[Resolution|resolution]] 3.17Å' scene=''> | <SX load='6n1h' size='340' side='right' viewer='molstar' caption='[[6n1h]], [[Resolution|resolution]] 3.17Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6n1h]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens | + | <table><tr><td colspan='2'>[[6n1h]] is a 16 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=6N1H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N1H FirstGlance]. <br> |
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.17Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.17Å</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=6n1h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n1h OCA], [https://pdbe.org/6n1h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n1h RCSB], [https://www.ebi.ac.uk/pdbsum/6n1h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n1h ProSAT]</span></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=6n1h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n1h OCA], [https://pdbe.org/6n1h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n1h RCSB], [https://www.ebi.ac.uk/pdbsum/6n1h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n1h ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/ASC_HUMAN ASC_HUMAN] Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the DAPIN and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome-mediated maturation of interleukin-1 beta. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing.<ref>PMID:19759850</ref> <ref>PMID:11103777</ref> <ref>PMID:12486103</ref> <ref>PMID:12646168</ref> <ref>PMID:15030775</ref> <ref>PMID:14730312</ref> <ref>PMID:16585594</ref> <ref>PMID:16982856</ref> <ref>PMID:17599095</ref> <ref>PMID:17349957</ref> <ref>PMID:16964285</ref> <ref>PMID:19234215</ref> <ref>PMID:19494289</ref> <ref>PMID:19158676</ref> <ref>PMID:19158675</ref> <ref>PMID:20482797</ref> <ref>PMID:21487011</ref> <ref>PMID:22732093</ref> <ref>PMID:14499617</ref> | [https://www.uniprot.org/uniprot/ASC_HUMAN ASC_HUMAN] Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the DAPIN and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome-mediated maturation of interleukin-1 beta. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing.<ref>PMID:19759850</ref> <ref>PMID:11103777</ref> <ref>PMID:12486103</ref> <ref>PMID:12646168</ref> <ref>PMID:15030775</ref> <ref>PMID:14730312</ref> <ref>PMID:16585594</ref> <ref>PMID:16982856</ref> <ref>PMID:17599095</ref> <ref>PMID:17349957</ref> <ref>PMID:16964285</ref> <ref>PMID:19234215</ref> <ref>PMID:19494289</ref> <ref>PMID:19158676</ref> <ref>PMID:19158675</ref> <ref>PMID:20482797</ref> <ref>PMID:21487011</ref> <ref>PMID:22732093</ref> <ref>PMID:14499617</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Canonical inflammasomes are cytosolic supramolecular complexes that activate caspase-1 upon sensing extrinsic microbial invasions and intrinsic sterile stress signals. During inflammasome assembly, adaptor proteins ASC and NLRC4 recruit caspase-1 through homotypic caspase recruitment domain (CARD) interactions, leading to caspase-1 dimerization and activation. Activated caspase-1 processes proinflammatory cytokines and Gasdermin D to induce cytokine maturation and pyroptotic cell death. Here, we present cryo-electron microscopy (cryo-EM) structures of NLRC4 CARD and ASC CARD filaments mediated by conserved three types of asymmetric interactions (types I, II, and III). We find that the CARDs of these two adaptor proteins share a similar assembly pattern, which matches that of the caspase-1 CARD filament whose structure we defined previously. These data indicate a unified mechanism for downstream caspase-1 recruitment through CARD-CARD interactions by both adaptors. Using structure modeling, we further show that full-length NLRC4 assembles via two separate symmetries at its CARD and its nucleotide-binding domain (NBD), respectively. | ||
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| + | Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1.,Li Y, Fu TM, Lu A, Witt K, Ruan J, Shen C, Wu H Proc Natl Acad Sci U S A. 2018 Oct 2. pii: 1810524115. doi:, 10.1073/pnas.1810524115. PMID:30279182<ref>PMID:30279182</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6n1h" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Cryo-EM structure of ASC-CARD filament
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Categories: Homo sapiens | Large Structures | Fu T | Li Y | Wu H
