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- PDB-6cb8: Cryo-EM structure of the Gasdermin A3 membrane pore -

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Basic information

Entry
Database: PDB / ID: 6cb8
TitleCryo-EM structure of the Gasdermin A3 membrane pore
ComponentsGasdermin-A3
KeywordsIMMUNE SYSTEM / Pyroptosis / Pore forming protein
Function / homology
Function and homology information


sebaceous gland cell differentiation / avascular cornea development in camera-type eye / negative regulation of timing of anagen / hair cycle / wide pore channel activity / mammary gland development / phosphatidylinositol-4-phosphate binding / positive regulation of extrinsic apoptotic signaling pathway / skin development / hair follicle morphogenesis ...sebaceous gland cell differentiation / avascular cornea development in camera-type eye / negative regulation of timing of anagen / hair cycle / wide pore channel activity / mammary gland development / phosphatidylinositol-4-phosphate binding / positive regulation of extrinsic apoptotic signaling pathway / skin development / hair follicle morphogenesis / phosphatidylserine binding / pyroptosis / somatic stem cell population maintenance / hair follicle development / extrinsic apoptotic signaling pathway / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of interleukin-1 beta production / mitochondrial membrane / negative regulation of canonical Wnt signaling pathway / defense response to bacterium / positive regulation of apoptotic process / perinuclear region of cytoplasm / membrane / nucleus / plasma membrane / cytosol
Similarity search - Function
Gasdermin, pore forming domain / Gasdermin pore forming domain / Gasdermin, PUB domain / Gasdermin PUB domain
Similarity search - Domain/homology
CARDIOLIPIN / Gasdermin-A3
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsRuan, J. / Wu, H.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Minority Health and Health Disparities (NIH/NIMHD)DP1HD087988 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01Al124491 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI123265 United States
CitationJournal: Nature / Year: 2018
Title: Cryo-EM structure of the gasdermin A3 membrane pore.
Authors: Jianbin Ruan / Shiyu Xia / Xing Liu / Judy Lieberman / Hao Wu /
Abstract: Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of ...Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of pore formation remains unresolved. Here we present the cryo-electron microscopy structures of the 27-fold and 28-fold single-ring pores formed by the N-terminal fragment of mouse GSDMA3 (GSDMA3-NT) at 3.8 and 4.2 Å resolutions, and of a double-ring pore at 4.6 Å resolution. In the 27-fold pore, a 108-stranded anti-parallel β-barrel is formed by two β-hairpins from each subunit capped by a globular domain. We identify a positively charged helix that interacts with the acidic lipid cardiolipin. GSDMA3-NT undergoes radical conformational changes upon membrane insertion to form long, membrane-spanning β-strands. We also observe an unexpected additional symmetric ring of GSDMA3-NT subunits that does not insert into the membrane in the double-ring pore, which may represent a pre-pore state of GSDMA3-NT. These structures provide a basis that explains the activities of several mutant gasdermins, including defective mutants that are associated with cancer.
History
DepositionFeb 2, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1May 9, 2018Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 16, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 3, 2018Group: Data collection / Refinement description / Category: refine
Revision 1.4Dec 18, 2019Group: Author supporting evidence / Other / Category: atom_sites / cell / pdbx_audit_support
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB / _pdbx_audit_support.funding_organization
Revision 1.5Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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Assembly

Deposited unit
A: Gasdermin-A3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8652
Polymers30,4011
Non-polymers1,4641
Water0
1
A: Gasdermin-A3
hetero molecules
x 27


Theoretical massNumber of molelcules
Total (without water)860,35754
Polymers820,82827
Non-polymers39,52927
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation26
Buried area300 Å2
ΔGint1 kcal/mol
Surface area13580 Å2
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit in distinct coordinate
  • point asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: C27 (27 fold cyclic))

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Components

#1: Protein Gasdermin-A3 / Gasdermin-3


Mass: 30401.035 Da / Num. of mol.: 1 / Fragment: residues 1-262
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Gsdma3, Gsdm3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q5Y4Y6
#2: Chemical ChemComp-CDL / CARDIOLIPIN / DIPHOSPHATIDYL GLYCEROL / BIS-(1,2-DIACYL-SN-GLYCERO-3-PHOSPHO)-1',3'-SN-GLYCEROL / Cardiolipin


Mass: 1464.043 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C81H156O17P2 / Comment: phospholipid*YM

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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: Gasdermin A3 N domain / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.81 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenConc.: 2 mg/ml / Embedding 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: (1.12_2829: ???) / Classification: refinement
EM softwareName: RELION / Version: 2 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C27 (27 fold cyclic)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 40086 / Symmetry type: POINT
RefinementResolution: 3.8→57.261 Å / SU ML: 0.56 / σ(F): 0.12 / Phase error: 39.43 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.3243 666 3.83 %
Rwork0.2874 --
obs0.2888 17377 98.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0041878
ELECTRON MICROSCOPYf_angle_d0.7732545
ELECTRON MICROSCOPYf_dihedral_angle_d4.8771141
ELECTRON MICROSCOPYf_chiral_restr0.046295
ELECTRON MICROSCOPYf_plane_restr0.006321
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.8003-4.09360.44251370.42123344ELECTRON MICROSCOPY99
4.0936-4.50540.34191240.31123307ELECTRON MICROSCOPY98
4.5054-5.1570.26811240.25063338ELECTRON MICROSCOPY98
5.157-6.49590.30031300.29513383ELECTRON MICROSCOPY100
6.4959-57.26730.32511510.25563339ELECTRON MICROSCOPY100

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