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- EMDB-8902: Cryo-EM Structures of ASC and NLRC4 CARD Filaments Reveal a Unifi... -

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Basic information

Entry
Database: EMDB / ID: EMD-8902
TitleCryo-EM Structures of ASC and NLRC4 CARD Filaments Reveal a Unified Mechanism of Nucleation and Activation of Caspase-1
Map dataHelical reconstruction of ASC-CARD filament
Sample
  • Organelle or cellular component: Caspase recruitment domain of Apoptosis-associated speck-like protein containing a CARD
    • Protein or peptide: Apoptosis-associated speck-like protein containing a CARD
Function / homology
Function and homology information


NLRP6 inflammasome complex / myosin I binding / Pyrin domain binding / myeloid dendritic cell activation involved in immune response / positive regulation of antigen processing and presentation of peptide antigen via MHC class II / negative regulation of protein serine/threonine kinase activity / regulation of intrinsic apoptotic signaling pathway / myeloid dendritic cell activation / IkappaB kinase complex / The AIM2 inflammasome ...NLRP6 inflammasome complex / myosin I binding / Pyrin domain binding / myeloid dendritic cell activation involved in immune response / positive regulation of antigen processing and presentation of peptide antigen via MHC class II / negative regulation of protein serine/threonine kinase activity / regulation of intrinsic apoptotic signaling pathway / myeloid dendritic cell activation / IkappaB kinase complex / The AIM2 inflammasome / AIM2 inflammasome complex / icosanoid biosynthetic process / NLRP1 inflammasome complex / macropinocytosis / canonical inflammasome complex / interleukin-6 receptor binding / BMP receptor binding / NLRP3 inflammasome complex assembly / positive regulation of adaptive immune response / NLRP3 inflammasome complex / cysteine-type endopeptidase activator activity / CLEC7A/inflammasome pathway / negative regulation of interferon-beta production / osmosensory signaling pathway / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of extrinsic apoptotic signaling pathway / pattern recognition receptor signaling pathway / positive regulation of macrophage cytokine production / negative regulation of NF-kappaB transcription factor activity / pattern recognition receptor activity / tropomyosin binding / pyroptotic inflammatory response / positive regulation of actin filament polymerization / positive regulation of release of cytochrome c from mitochondria / positive regulation of activated T cell proliferation / intrinsic apoptotic signaling pathway by p53 class mediator / The NLRP3 inflammasome / positive regulation of interleukin-10 production / cellular response to interleukin-1 / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of T cell migration / positive regulation of DNA-binding transcription factor activity / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / positive regulation of defense response to virus by host / negative regulation of canonical NF-kappaB signal transduction / negative regulation of cytokine production involved in inflammatory response / intrinsic apoptotic signaling pathway / activation of innate immune response / positive regulation of phagocytosis / positive regulation of interleukin-1 beta production / tumor necrosis factor-mediated signaling pathway / positive regulation of interleukin-8 production / positive regulation of JNK cascade / apoptotic signaling pathway / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of NF-kappaB transcription factor activity / protein homooligomerization / positive regulation of T cell activation / regulation of protein stability / positive regulation of interleukin-6 production / positive regulation of type II interferon production / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / SARS-CoV-1 activates/modulates innate immune responses / cellular response to tumor necrosis factor / azurophil granule lumen / cellular response to lipopolysaccharide / regulation of inflammatory response / protease binding / secretory granule lumen / defense response to Gram-negative bacterium / defense response to virus / microtubule / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / positive regulation of canonical NF-kappaB signal transduction / protein dimerization activity / defense response to Gram-positive bacterium / regulation of autophagy / positive regulation of apoptotic process / inflammatory response / Golgi membrane / innate immune response / neuronal cell body / apoptotic process / Neutrophil degranulation / nucleolus / enzyme binding / endoplasmic reticulum / signal transduction / protein homodimerization activity / protein-containing complex / mitochondrion / extracellular region / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
CARD8/ASC/NALP1, CARD domain / : / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / PAAD/DAPIN/Pyrin domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Death-like domain superfamily
Similarity search - Domain/homology
Apoptosis-associated speck-like protein containing a CARD
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsLi Y / Fu T / Wu H
CitationJournal: Proc Natl Acad Sci U S A / Year: 2018
Title: Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1.
Authors: Yang Li / Tian-Min Fu / Alvin Lu / Kristen Witt / Jianbin Ruan / Chen Shen / Hao Wu /
Abstract: Canonical inflammasomes are cytosolic supramolecular complexes that activate caspase-1 upon sensing extrinsic microbial invasions and intrinsic sterile stress signals. During inflammasome assembly, ...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.
History
DepositionJun 12, 2018-
Header (metadata) releaseJun 27, 2018-
Map releaseOct 10, 2018-
UpdateDec 5, 2018-
Current statusDec 5, 2018Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6n1h
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6n1h
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8902.png

Downloads & links

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Map

FileDownload / File: emd_8902.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHelical reconstruction of ASC-CARD filament
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.32 Å/pix.
x 192 pix.
= 253.44 Å		1.32 Å/pix.
x 192 pix.
= 253.44 Å		1.32 Å/pix.
x 192 pix.
= 253.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.32 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1 / Movie #1: 0.1
Minimum - Maximum-0.3005335 - 0.5332551
Average (Standard dev.)0.0026573783 (±0.025429418)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-95-95-95
Dimensions192192192
Spacing192192192
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.321.321.32
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z253.440253.440253.440
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS-95-95-95
NC/NR/NS192192192
D min/max/mean-0.3010.5330.003

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Supplemental data

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Sample components

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Entire : Caspase recruitment domain of Apoptosis-associated speck-like pro...

EntireName: Caspase recruitment domain of Apoptosis-associated speck-like protein containing a CARD
Components
  • Organelle or cellular component: Caspase recruitment domain of Apoptosis-associated speck-like protein containing a CARD
    • Protein or peptide: Apoptosis-associated speck-like protein containing a CARD

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Supramolecule #1: Caspase recruitment domain of Apoptosis-associated speck-like pro...

SupramoleculeName: Caspase recruitment domain of Apoptosis-associated speck-like protein containing a CARD
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)

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Macromolecule #1: Apoptosis-associated speck-like protein containing a CARD

MacromoleculeName: Apoptosis-associated speck-like protein containing a CARD
type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.775143 KDa
Recombinant expressionOrganism: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
SequenceString:
LHFIDQHRAA LIARVTNVEW LLDALYGKVL TDEQYQAVRA EPTNPSKMRK LFSFTPAWNW TCKDLLLQAL RESQSYLVED LER

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 5.0 Å
Applied symmetry - Helical parameters - Δ&Phi: -100.58 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 264167
Final angle assignmentType: NOT APPLICABLE

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