Structure and assembly of a bacterial gasdermin pore

• 成果类型: Article
• 署名作者: Johnson, Alex G.; Mayer, Megan L.; Schaefer, Stefan L.; McNamara-Bordewick, Nora K.; Hummer, Gerhard; Kranzusch, Philip J.
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Max Planck Society; Goethe University Frankfurt; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3946
• DOI: 10.1038/s41586-024-07216-3
• 发表日期: 2024-04-18
• 关键词: molecular-dynamics; software news; transitions; mechanism; toxin

摘要

In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis(1-3). Studies of human and mouse GSDM pores have revealed the functions and architectures of assemblies comprising 24 to 33 protomers(4-9), 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 more than 50 protomers. We determine a cryo-electron microscopy structure of a Vitiosangium bGSDM in an active 'slinky'-like oligomeric conformation and analyse 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 beta-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.