Structure and assembly of a bacterial gasdermin pore.

Autor: Johnson AG; Department of Microbiology, Harvard Medical School, Boston, MA, USA. algejohnson@gmail.com.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. algejohnson@gmail.com., Mayer ML; Harvard Center for Cryo-Electron Microscopy, Harvard Medical School, Boston, MA, USA., Schaefer SL; Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany., McNamara-Bordewick NK; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Hummer G; Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.; Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany., Kranzusch PJ; Department of Microbiology, Harvard Medical School, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Apr; Vol. 628 (8008), pp. 657-663. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1038/s41586-024-07216-3
Abstrakt: 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 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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