+Open data
-Basic information
Entry | Database: PDB / ID: 8spb | |||||||||
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Title | Caspase-4/Pro-IL-18 complex | |||||||||
Components |
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Keywords | IMMUNE SYSTEM / Innate immune / Complex | |||||||||
Function / homology | Function and homology information caspase-4 / non-canonical inflammasome complex / positive regulation of interleukin-18-mediated signaling pathway / interleukin-18 receptor binding / non-canonical inflammasome complex assembly / Interleukin-18 signaling / positive regulation of tissue remodeling / AIM2 inflammasome complex / IPAF inflammasome complex / NLRP1 inflammasome complex ...caspase-4 / non-canonical inflammasome complex / positive regulation of interleukin-18-mediated signaling pathway / interleukin-18 receptor binding / non-canonical inflammasome complex assembly / Interleukin-18 signaling / positive regulation of tissue remodeling / AIM2 inflammasome complex / IPAF inflammasome complex / NLRP1 inflammasome complex / positive regulation of T-helper 2 cell differentiation / positive regulation of T-helper 1 cell cytokine production / NLRP3 inflammasome complex / positive regulation of macrophage derived foam cell differentiation / CARD domain binding / caspase binding / positive regulation of interleukin-13 production / positive regulation of neuroinflammatory response / interleukin-18-mediated signaling pathway / natural killer cell mediated cytotoxicity / negative regulation of myoblast differentiation / type 2 immune response / natural killer cell activation / sleep / neutrophil activation / positive regulation of tumor necrosis factor-mediated signaling pathway / Interleukin-1 processing / positive regulation of NK T cell proliferation / triglyceride homeostasis / positive regulation of natural killer cell proliferation / positive regulation of granulocyte macrophage colony-stimulating factor production / T-helper 1 type immune response / positive regulation of activated T cell proliferation / pyroptotic inflammatory response / positive regulation of interleukin-17 production / Interleukin-10 signaling / protein autoprocessing / protein maturation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / establishment of skin barrier / Pyroptosis / regulation of cell adhesion / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway / cytokine activity / cholesterol homeostasis / lipopolysaccharide binding / positive regulation of smooth muscle cell proliferation / NOD1/2 Signaling Pathway / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to amyloid-beta / positive regulation of type II interferon production / positive regulation of neuron apoptotic process / cell-cell signaling / positive regulation of cold-induced thermogenesis / positive regulation of NF-kappaB transcription factor activity / regulation of inflammatory response / cellular response to lipopolysaccharide / angiogenesis / Interleukin-4 and Interleukin-13 signaling / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / cysteine-type endopeptidase activity / innate immune response / lipid binding / apoptotic process / endoplasmic reticulum membrane / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / proteolysis / extracellular space / extracellular region / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Pascal, D. / Dong, Y. / Wu, H. / Jon, K. | |||||||||
Funding support | United States, 1items
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Citation | Journal: Nature / Year: 2023 Title: Structural insights into cytokine cleavage by inflammatory caspase-4. Authors: Pascal Devant / Ying Dong / Julian Mintseris / Weiyi Ma / Steven P Gygi / Hao Wu / Jonathan C Kagan / Abstract: Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines. Despite the biological importance, the structural ...Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines. Despite the biological importance, the structural basis for inflammatory caspase-mediated cytokine processing has remained unclear. To date, catalytic cleavage of IL-1-family members, including pro-IL-1β and pro-IL-18, has been attributed primarily to caspase-1 activities within canonical inflammasomes. Here we demonstrate that the lipopolysaccharide receptor caspase-4 from humans and other mammalian species (except rodents) can cleave pro-IL-18 with an efficiency similar to pro-IL-1β and pro-IL-18 cleavage by the prototypical IL-1-converting enzyme caspase-1. This ability of caspase-4 to cleave pro-IL-18, combined with its previously defined ability to cleave and activate the lytic pore-forming protein gasdermin D (GSDMD), enables human cells to bypass the need for canonical inflammasomes and caspase-1 for IL-18 release. The structure of the caspase-4-pro-IL-18 complex determined using cryogenic electron microscopy reveals that pro-lL-18 interacts with caspase-4 through two distinct interfaces: a protease exosite and an interface at the caspase-4 active site involving residues in the pro-domain of pro-IL-18, including the tetrapeptide caspase-recognition sequence. The mechanisms revealed for cytokine substrate capture and cleavage differ from those observed for the caspase substrate GSDMD. These findings provide a structural framework for the discussion of caspase activities in health and disease. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8spb.cif.gz | 160.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8spb.ent.gz | 124.3 KB | Display | PDB format |
PDBx/mmJSON format | 8spb.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8spb_validation.pdf.gz | 979.3 KB | Display | wwPDB validaton report |
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Full document | 8spb_full_validation.pdf.gz | 979.8 KB | Display | |
Data in XML | 8spb_validation.xml.gz | 32.6 KB | Display | |
Data in CIF | 8spb_validation.cif.gz | 46.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/sp/8spb ftp://data.pdbj.org/pub/pdb/validation_reports/sp/8spb | HTTPS FTP |
-Related structure data
Related structure data | 40678MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 23353.363 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CASP4, ICH2 / Production host: Escherichia coli B (bacteria) / References: UniProt: P49662 #2: Protein | Mass: 10770.386 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CASP4, ICH2 / Production host: Escherichia coli B (bacteria) / References: UniProt: P49662 #3: Protein | Mass: 21850.641 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IL18 / Plasmid: pTIE1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q14116 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: caspase-4 in complex with pro-IL-18 / Type: COMPLEX / Entity ID: #1, #3, #2 / Source: MULTIPLE SOURCES |
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Molecular weight | Value: 0.144 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli B (bacteria) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: NONE | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200000 / Symmetry type: POINT | ||||||||||||||||||||||||
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