Structure and assembly of a bacterial gasdermin pore

  • In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1–3. Studies of human and mouse GSDM pores reveal the functions and architectures of 24–33 protomers assemblies4–9, 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 >50 protomers. We determine a 3.3 Å cryo-EM structure of a Vitiosangium 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, we define a stepwise model of GSDM pore assembly and demonstrate that pore formation is driven by local unfolding of membrane-spanning β-strand regions and pre-insertion of a covalently bound palmitoyl into the target membrane. These results yield insights into the diversity of GSDM pores found in nature and the function of an ancient post-translational modification in enabling a programmed host cell death process.

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Metadaten
Author:Alex G. JohnsonORCiD, Megan L. MayerORCiD, Stefan L. SchaeferORCiD, Nora K. McNamara-BordewickORCiD, Gerhard HummerORCiD, Philip J. KranzuschORCiD
URN:urn:nbn:de:hebis:30:3-794623
URL:https://www.biorxiv.org/content/10.1101/2023.04.20.537723v1
DOI:https://doi.org/10.1101/2023.04.20.537723
Parent Title (English):bioRxiv
Publisher:bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2023/04/20
Date of first Publication:2023/04/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/07/16
Issue:2023.04.20.537723, Version 1
Edition:Version 1
Page Number:28
HeBIS-PPN:520535588
Institutes:Physik / Physik
Angeschlossene und kooperierende Institutionen / MPI für Biophysik
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International