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- EMDB-34258: Cryo-EM structure of the gasdermin B pore -

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Basic information

Entry
Database: EMDB / ID: EMD-34258
TitleCryo-EM structure of the gasdermin B pore
Map data
Sample
  • Complex: Pore-forming protein gasdermin B
    • Protein or peptide: Isoform 4 of Gasdermin-B
Function / homology
Function and homology information


cytotoxic T cell pyroptotic cell death / wide pore channel activity / killing by host of symbiont cells / cardiolipin binding / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptotic inflammatory response / phosphatidylinositol-4,5-bisphosphate binding / phospholipid binding / killing of cells of another organism ...cytotoxic T cell pyroptotic cell death / wide pore channel activity / killing by host of symbiont cells / cardiolipin binding / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptotic inflammatory response / phosphatidylinositol-4,5-bisphosphate binding / phospholipid binding / killing of cells of another organism / defense response to Gram-negative bacterium / defense response to bacterium / plasma membrane / cytoplasm
Similarity search - Function
Gasdermin, PUB domain / Gasdermin PUB domain / Gasdermin, pore forming domain / Gasdermin pore forming domain
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsHou YJ / Cheng H / Ding J
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nature / Year: 2023
Title: Structural mechanisms for regulation of GSDMB pore-forming activity.
Authors: Xiu Zhong / Huan Zeng / Zhiwei Zhou / Ya Su / Hang Cheng / Yanjie Hou / Yang She / Na Feng / Jia Wang / Feng Shao / Jingjin Ding /
Abstract: Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. GSDMB and the charter gasdermin family member GSDMD have been ...Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. GSDMB and the charter gasdermin family member GSDMD have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. ). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently. Here we report the crystal structure of the IpaH7.8-GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins. GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies. Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.
History
DepositionSep 8, 2022-
Header (metadata) releaseApr 12, 2023-
Map releaseApr 12, 2023-
UpdateMay 3, 2023-
Current statusMay 3, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34258.png

Downloads & links

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Map

FileDownload / File: emd_34258.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.365
Minimum - Maximum-1.2281204 - 2.4491806
Average (Standard dev.)-0.00015990813 (±0.04347619)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 552.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34258_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34258_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Pore-forming protein gasdermin B

EntireName: Pore-forming protein gasdermin B
Components
  • Complex: Pore-forming protein gasdermin B
    • Protein or peptide: Isoform 4 of Gasdermin-B

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Supramolecule #1: Pore-forming protein gasdermin B

SupramoleculeName: Pore-forming protein gasdermin B / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 4 of Gasdermin-B

MacromoleculeName: Isoform 4 of Gasdermin-B / type: protein_or_peptide / ID: 1 / Number of copies: 27 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.628705 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SGRPMFSVFE EITRIVVKEM DAGGDMIAVR SLVDADRFRC FHLVGEKRTF FGCRHYTTGL TLMDILDTDG DKWLDELDSG LQGQKAEFQ ILDNVDSTGE LIVRLPKEIT ISGSFQGFHH QKIKISENRI SQQYLATLEN RKLKRELPFS FRSINTRENL Y LVTETLET ...String:
SGRPMFSVFE EITRIVVKEM DAGGDMIAVR SLVDADRFRC FHLVGEKRTF FGCRHYTTGL TLMDILDTDG DKWLDELDSG LQGQKAEFQ ILDNVDSTGE LIVRLPKEIT ISGSFQGFHH QKIKISENRI SQQYLATLEN RKLKRELPFS FRSINTRENL Y LVTETLET VKEETLKSDR QYKFWSQISQ GHLSYKHKGQ REVTIPPNRV LSYRVKQLVF PNKETMNIHF RGKTKSFPEG KS LEVLFQ

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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

Concentration0.1 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 85337
FSC plot (resolution estimation)

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