Cryo-EM structure of the gasdermin A3 membrane pore

Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Cryoelectron Microscopy*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Lipids / metabolism
  • Mice
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / ultrastructure
  • Mutation
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / ultrastructure
  • Neoplasms / genetics
  • Perforin / chemistry
  • Perforin / metabolism
  • Phosphate-Binding Proteins
  • Protein Conformation
  • Protein Folding
  • Protein Multimerization
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / ultrastructure*
  • Structure-Activity Relationship


  • GSDMD protein, human
  • Gsdma3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Lipids
  • Mutant Proteins
  • Neoplasm Proteins
  • Phosphate-Binding Proteins
  • Protein Subunits
  • Proteins
  • Perforin