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- PDB-8spb: Caspase-4/Pro-IL-18 complex -

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Basic information

Entry
Database: PDB / ID: 8spb
TitleCaspase-4/Pro-IL-18 complex
Components
  • Caspase-4 subunit p10
  • Caspase-4 subunit p20
  • Interleukin-18
KeywordsIMMUNE SYSTEM / Innate immune / Complex
Function / homology
Function and homology information


caspase-4 / non-canonical inflammasome complex / interleukin-18 receptor binding / positive regulation of interleukin-18-mediated signaling pathway / non-canonical inflammasome complex assembly / Interleukin-18 signaling / positive regulation of tissue remodeling / NLRP1 inflammasome complex / positive regulation of T-helper 1 cell cytokine production / positive regulation of T-helper 2 cell differentiation ...caspase-4 / non-canonical inflammasome complex / interleukin-18 receptor binding / positive regulation of interleukin-18-mediated signaling pathway / non-canonical inflammasome complex assembly / Interleukin-18 signaling / positive regulation of tissue remodeling / NLRP1 inflammasome complex / positive regulation of T-helper 1 cell cytokine production / positive regulation of T-helper 2 cell differentiation / CARD domain binding / positive regulation of interleukin-13 production / interleukin-18-mediated signaling pathway / positive regulation of neuroinflammatory response / neutrophil activation / positive regulation of NK T cell proliferation / negative regulation of myoblast differentiation / Interleukin-1 processing / positive regulation of natural killer cell proliferation / positive regulation of tumor necrosis factor-mediated signaling pathway / sleep / positive regulation of macrophage derived foam cell differentiation / triglyceride homeostasis / natural killer cell activation / positive regulation of granulocyte macrophage colony-stimulating factor production / type 2 immune response / positive regulation of tyrosine phosphorylation of STAT protein / T-helper 1 type immune response / natural killer cell mediated cytotoxicity / pyroptotic inflammatory response / Interleukin-10 signaling / positive regulation of interleukin-17 production / positive regulation of activated T cell proliferation / protein autoprocessing / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Pyroptosis / establishment of skin barrier / regulation of cell adhesion / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / intrinsic apoptotic signaling pathway / protein maturation / cholesterol homeostasis / cytokine activity / positive regulation of smooth muscle cell proliferation / lipopolysaccharide binding / positive regulation of non-canonical NF-kappaB signal transduction / NOD1/2 Signaling Pathway / cytokine-mediated signaling pathway / positive regulation of type II interferon production / positive regulation of inflammatory response / cellular response to amyloid-beta / positive regulation of NF-kappaB transcription factor activity / positive regulation of neuron apoptotic process / cell-cell signaling / positive regulation of cold-induced thermogenesis / cellular response to lipopolysaccharide / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / angiogenesis / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / defense response to Gram-positive bacterium / defense response to bacterium / immune response / inflammatory response / innate immune response / cysteine-type endopeptidase activity / apoptotic process / lipid binding / endoplasmic reticulum membrane / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / proteolysis / extracellular space / extracellular region / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Interleukin-18 / Interleukin-1 family / Interleukin-1 / 18 / Caspase recruitment domain / Cytokine IL1/FGF / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase C14 family / Peptidase family C14A, His active site ...Interleukin-18 / Interleukin-1 family / Interleukin-1 / 18 / Caspase recruitment domain / Cytokine IL1/FGF / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase C14 family / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Death-like domain superfamily
Similarity search - Domain/homology
Caspase-4 / Interleukin-18
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsPascal, D. / Dong, Y. / Wu, H. / Jon, K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD) United States
CitationJournal: 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
DepositionMay 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.0Nov 22, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 22, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Nov 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.0Nov 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.0Nov 22, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 22, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Nov 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 2.0Nov 29, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / struct_conf / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _atom_site.label_seq_id / _entity.formula_weight ..._atom_site.label_seq_id / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Description: Atomic clashes / Provider: author / Type: Coordinate replacement
Revision 2.1Dec 6, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 2.2Dec 27, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.3May 21, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-4 subunit p20
B: Caspase-4 subunit p10
C: Interleukin-18
a: Caspase-4 subunit p20
b: Caspase-4 subunit p10
c: Interleukin-18


Theoretical massNumber of molelcules
Total (without water)111,9496
Polymers111,9496
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Caspase-4 subunit p20


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 Caspase-4 subunit p10


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 Interleukin-18


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
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: caspase-4 in complex with pro-IL-18 / Type: COMPLEX / Entity ID: #1, #3, #2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.144 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli B (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036472
ELECTRON MICROSCOPYf_angle_d0.4438706
ELECTRON MICROSCOPYf_dihedral_angle_d4.074840
ELECTRON MICROSCOPYf_chiral_restr0.042964
ELECTRON MICROSCOPYf_plane_restr0.0031124

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