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- EMDB-21160: Gasdermin D pore -

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Basic information

Entry
Database: EMDB / ID: EMD-21160
TitleGasdermin D pore
Map dataPore-forming protein Gasdermin-D
Sample
  • Complex: Pore-forming protein Gasdermin-D
    • Protein or peptide: Gasdermin-D, N-terminal
Function / homology
Function and homology information


pore complex assembly / : / Release of apoptotic factors from the mitochondria / wide pore channel activity / NLRP3 inflammasome complex / cardiolipin binding / Regulation of TLR by endogenous ligand / phosphatidic acid binding / Interleukin-1 processing / phosphatidylinositol-4-phosphate binding ...pore complex assembly / : / Release of apoptotic factors from the mitochondria / wide pore channel activity / NLRP3 inflammasome complex / cardiolipin binding / Regulation of TLR by endogenous ligand / phosphatidic acid binding / Interleukin-1 processing / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptosis / protein secretion / Pyroptosis / Purinergic signaling in leishmaniasis infection / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of interleukin-1 beta production / mitochondrial membrane / protein homooligomerization / positive regulation of inflammatory response / specific granule lumen / tertiary granule lumen / defense response to Gram-negative bacterium / ficolin-1-rich granule lumen / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / innate immune response / Neutrophil degranulation / extracellular space / extracellular region / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
Gasdermin, pore forming domain / Gasdermin pore forming domain / Gasdermin, PUB domain / Gasdermin PUB domain
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsXia S / Ruan J / Wu H
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI139914 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)DP1HD087988 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI124491 United States
CitationJournal: Nature / Year: 2021
Title: Gasdermin D pore structure reveals preferential release of mature interleukin-1.
Authors: Shiyu Xia / Zhibin Zhang / Venkat Giri Magupalli / Juan Lorenzo Pablo / Ying Dong / Setu M Vora / Longfei Wang / Tian-Min Fu / Matthew P Jacobson / Anna Greka / Judy Lieberman / Jianbin Ruan / Hao Wu /
Abstract: As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the ...As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
History
DepositionJan 3, 2020-
Header (metadata) releaseApr 21, 2021-
Map releaseApr 21, 2021-
UpdateJun 16, 2021-
Current statusJun 16, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vfe
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6vfe
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21160.png

Downloads & links

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Map

FileDownload / File: emd_21160.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPore-forming protein Gasdermin-D
Voxel sizeX=Y=Z: 1.7 Å
Density
Contour LevelBy AUTHOR: 0.013 / Movie #1: 0.013
Minimum - Maximum-0.055482913 - 0.11992676
Average (Standard dev.)0.00044610424 (±0.0040871436)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 408.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.71.71.7
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z408.000408.000408.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0550.1200.000

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Supplemental data

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Sample components

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Entire : Pore-forming protein Gasdermin-D

EntireName: Pore-forming protein Gasdermin-D
Components
  • Complex: Pore-forming protein Gasdermin-D
    • Protein or peptide: Gasdermin-D, N-terminal

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Supramolecule #1: Pore-forming protein Gasdermin-D

SupramoleculeName: Pore-forming protein Gasdermin-D / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
Molecular weightExperimental: 1 MDa

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Macromolecule #1: Gasdermin-D, N-terminal

MacromoleculeName: Gasdermin-D, N-terminal / type: protein_or_peptide / ID: 1 / Number of copies: 33 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.850221 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSAFERVVR RVVQELDHGG EFIPVTSLQS STGFQPYCLV VRKPSSSWFW KPRYKCVNLS IKDILEPDAA EPDVQRGRSF HFYDAMDGQ IQGSVELAAP GQAKIAGGAA VSDSSSTSMN VYSLSVDPNT WQTLLHERHL RQPEHKVLQQ LRSRGDNVYV V TEVLQTQK ...String:
MGSAFERVVR RVVQELDHGG EFIPVTSLQS STGFQPYCLV VRKPSSSWFW KPRYKCVNLS IKDILEPDAA EPDVQRGRSF HFYDAMDGQ IQGSVELAAP GQAKIAGGAA VSDSSSTSMN VYSLSVDPNT WQTLLHERHL RQPEHKVLQQ LRSRGDNVYV V TEVLQTQK EVEVTRTHKR EGSGRFSLPG ATCEQGEGQG HLSQKKTVTI PSGSTLAFRV AQLVIDSDLD VLLFPDKKQR TF Q

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 63.25 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionApplied symmetry - Point group: C33 (33 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 90222
FSC plot (resolution estimation)

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