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-Structure paper
Title | Structure and assembly of a bacterial gasdermin pore. |
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Journal, issue, pages | bioRxiv, Year 2023 |
Publish date | Oct 26, 2023 |
Authors | Alex G Johnson / Megan L Mayer / Stefan L Schaefer / Nora K McNamara-Bordewick / Gerhard Hummer / Philip J Kranzusch / |
PubMed Abstract | In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis. Studies of human and mouse GSDM pores reveal the functions ...In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis. Studies of human and mouse GSDM pores reveal the functions and architectures of 24-33 protomers assemblies, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing >50 protomers. We determine a 3.3 Å cryo-EM structure of a bGSDM in an active slinky-like oligomeric conformation and analyze bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, our results support a stepwise model of GSDM pore assembly and suggest that a covalently bound palmitoyl can leave a hydrophobic sheath and insert into the membrane before formation of the membrane-spanning β-strand regions. These results reveal the diversity of GSDM pores found in nature and explain the function of an ancient post-translational modification in enabling programmed host cell death. |
External links | bioRxiv / PubMed:37131678 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.0 - 7.3 Å |
Structure data | EMDB-43508: Structure of a bacterial gasdermin small oval pore assembly EMDB-43511: Structure of a bacterial gasdermin double pore assembly EMDB-43513: Structure of a bacterial gasdermin slinky-like oligomer from a heterogeneous sample |
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