Nature (London), 2018-05, Vol.557 (7703), p.62-67
2018
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- Autor(en) / Beteiligte
- Titel
- Cryo-EM structure of the gasdermin A3 membrane pore
- Ist Teil von
- Nature (London), 2018-05, Vol.557 (7703), p.62-67
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/s41586-018-0058-6Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6007975
- Format
- –
- Schlagworte
- Animals, Apoptosis, Biochemistry, Cancer, Cardiolipin, Cell death, Cell Membrane - metabolism, Cryoelectron Microscopy, Electron microscopy, Enzymes, Humans, Inflammation, Lipids, Membrane lipids, Membrane Lipids - metabolism, Membrane proteins, Membranes, Mice, Microscopy, Models, Molecular, Mutant Proteins - chemistry, Mutant Proteins - genetics, Mutant Proteins - ultrastructure, Mutants, Mutation, Neoplasm Proteins - chemistry, Neoplasm Proteins - metabolism, Neoplasm Proteins - ultrastructure, Neoplasms - genetics, Neural networks, Observations, Perforin - chemistry, Perforin - metabolism, Physiological aspects, Pore formation, Pores, Protein Conformation, Protein Folding, Protein Multimerization, Protein Subunits - chemistry, Protein Subunits - metabolism, Proteins, Proteins - chemistry, Proteins - genetics, Proteins - metabolism, Proteins - ultrastructure, Rings (mathematics), Structure, Structure-Activity Relationship, Symmetry