TY  - INPR
A1  - Johnson, Alex G.
A1  - Mayer, Megan L.
A1  - Schaefer, Stefan L.
A1  - McNamara-Bordewick, Nora K.
A1  - Hummer, Gerhard
A1  - Kranzusch, Philip J.
T1  - Structure and assembly of a bacterial gasdermin pore
T2  - bioRxiv
N2  - 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.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79462
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-794623
UR  - https://www.biorxiv.org/content/10.1101/2023.04.20.537723v1
IS  - 2023.04.20.537723, Version 1
PB  - bioRxiv
ER  -