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- PDB-8efp: CryoEM structure of GSDMB in complex with shigella IpaH7.8 -

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Basic information

Entry
Database: PDB / ID: 8efp
TitleCryoEM structure of GSDMB in complex with shigella IpaH7.8
Components
  • Gasdermin-B
  • Probable E3 ubiquitin-protein ligase ipaH7.8
KeywordsTRANSFERASE/LIPID BINDING PROTEIN / GSDMB / GSDMD / pyroptosis / ubiquitination / ANTIMICROBIAL PROTEIN / TRANSFERASE-LIPID BINDING PROTEIN complex
Function / homology
Function and homology information


symbiont-mediated suppression of host programmed cell death / cytotoxic T cell pyroptotic cell death / effector-mediated activation of programmed cell death in host / wide pore channel activity / killing by host of symbiont cells / programmed cell death / cardiolipin binding / phosphatidylinositol-4-phosphate binding / pyroptotic inflammatory response / phosphatidylserine binding ...symbiont-mediated suppression of host programmed cell death / cytotoxic T cell pyroptotic cell death / effector-mediated activation of programmed cell death in host / wide pore channel activity / killing by host of symbiont cells / programmed cell death / cardiolipin binding / phosphatidylinositol-4-phosphate binding / pyroptotic inflammatory response / phosphatidylserine binding / phosphatidylinositol-4,5-bisphosphate binding / RING-type E3 ubiquitin transferase / phospholipid binding / ubiquitin protein ligase activity / ubiquitin-dependent protein catabolic process / defense response to Gram-negative bacterium / host cell cytoplasm / killing of cells of another organism / defense response to bacterium / protein ubiquitination / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Novel E3 ligase domain / C-terminal novel E3 ligase, LRR-interacting / LRR-containing bacterial E3 ligase, N-terminal / Type III secretion system leucine rich repeat protein / : / Gasdermin, PUB domain / Gasdermin PUB domain / Gasdermin, pore forming domain / Gasdermin pore forming domain / Leucine-rich repeats, bacterial type ...Novel E3 ligase domain / C-terminal novel E3 ligase, LRR-interacting / LRR-containing bacterial E3 ligase, N-terminal / Type III secretion system leucine rich repeat protein / : / Gasdermin, PUB domain / Gasdermin PUB domain / Gasdermin, pore forming domain / Gasdermin pore forming domain / Leucine-rich repeats, bacterial type / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase ipaH7.8 / Gasdermin-B
Similarity search - Component
Biological speciesShigella flexneri (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsWang, C. / Ruan, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nature / Year: 2023
Title: Structural basis for GSDMB pore formation and its targeting by IpaH7.8.
Authors: Chengliang Wang / Sonia Shivcharan / Tian Tian / Skylar Wright / Danyang Ma / JengYih Chang / Kunpeng Li / Kangkang Song / Chen Xu / Vijay A Rathinam / Jianbin Ruan /
Abstract: Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of ...Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity. Shigella, an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated host defence by secreting IpaH7.8, a virulence effector that triggers ubiquitination-dependent proteasomal degradation of GSDMB. Here, we report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore. The structure of the GSDMB-IpaH7.8 complex identifies a motif of three negatively charged residues in GSDMB as the structural determinant recognized by IpaH7.8. Human, but not mouse, GSDMD contains this conserved motif, explaining the species specificity of IpaH7.8. The GSDMB pore structure shows the alternative splicing-regulated interdomain linker in GSDMB as a regulator of GSDMB pore formation. GSDMB isoforms with a canonical interdomain linker exhibit normal pyroptotic activity whereas other isoforms exhibit attenuated or no pyroptotic activity. Overall, this work sheds light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and shows a structural determinant in GSDMB critical for its pyroptotic activity.
History
DepositionSep 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2May 3, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Probable E3 ubiquitin-protein ligase ipaH7.8
C: Gasdermin-B


Theoretical massNumber of molelcules
Total (without water)112,0142
Polymers112,0142
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Probable E3 ubiquitin-protein ligase ipaH7.8 / Probable RING-type E3 ubiquitin transferase ipaH7.8


Mass: 64602.949 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Shigella flexneri (bacteria) / Gene: ipaH7.8, CP0078, pWR501_0084, SFLP133 / Production host: Escherichia coli (E. coli)
References: UniProt: P18014, RING-type E3 ubiquitin transferase
#2: Protein Gasdermin-B / Gasdermin-like protein


Mass: 47410.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSDMB, GSDML, PP4052, PRO2521 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8TAX9

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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

Component
IDNameTypeEntity IDParent-IDSource
1GSDMB-IpaH7.8COMPLEXall0RECOMBINANT
2E3 ubiquitin-protein ligase ipaH7.8COMPLEX#11RECOMBINANT
3Gasdermin-BCOMPLEX#21RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Shigella flexneri (bacteria)623
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 66.95 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113959 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0054849
ELECTRON MICROSCOPYf_angle_d1.1136566
ELECTRON MICROSCOPYf_dihedral_angle_d7.499638
ELECTRON MICROSCOPYf_chiral_restr0.053752
ELECTRON MICROSCOPYf_plane_restr0.008855

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