43DQ
GSDME-NT Pore
Summary for 43DQ
| Entry DOI | 10.2210/pdb43dq/pdb |
| EMDB information | 81795 |
| Descriptor | Gasdermin-E (1 entity in total) |
| Functional Keywords | gsdme-nt pore, pyroptosis, apoptosis, pore-forming protein, cryo-em |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 28 |
| Total formula weight | 768638.50 |
| Authors | |
| Primary citation | Du, G.,Ehrmann, J.F.,Lieberman, J.,Wu, H. Structural basis of GSDME pore formation and its regulation by S-palmitoylation. Proc.Natl.Acad.Sci.USA, 123:e2614339123-e2614339123, 2026 Cited by PubMed Abstract: Pyroptosis is defined as gasdermin-mediated lytic programmed cell death. Gasdermin E (GSDME), a substrate of the apoptotic caspase-3, can convert apoptosis into pyroptosis, with critical roles in antitumor immunity and chemotherapy-induced tissue damage. Despite its importance, the structural mechanism of GSDME pore formation and its regulation by posttranslational modifications remain largely unknown. Here, we present the cryo-electron microscopy (cryo-EM) structure at 3.16 Å resolution of the human GSDME N-terminal (NT) pore using proteins expressed from mammalian cells. The structure reveals a GSDME-NT pore assembled mainly as a 28-subunit homo-oligomer, and a dramatic conformational rearrangement from the autoinhibited state, with refolding of the two β-hairpins in each monomer to form a membrane-spanning β-barrel with an acidic conduit. Unexpectedly, we identify endogenous S-palmitoylation of C45, C168, and C180, required for membrane binding and pore formation. In addition, extra cryo-EM densities are visible adjacent to the C45 side chain, potentially corresponding to the flexibly linked palmitate chain. Structure-guided mutagenesis demonstrates that these palmitoylation sites synergistically control pore formation. The structure served as a molecular blueprint for analyzing cancer-associated mutations, known to disrupt GSDME function. These mutations cluster at functional hotspots in the oligomerization interfaces, membrane-contact regions, and the β-barrel, where they disrupt pore integrity. Collectively, our findings establish palmitoylation as an obligatory licensing step for membrane binding and pore formation, provide structural visualization of a palmitoylated gasdermin, and reveal how cancer-associated mutations impair pyroptotic function. This structure and these insights will be useful for developing strategies that target GSDME to treat cancer and inflammatory disease. PubMed: 42636365DOI: 10.1073/pnas.2614339123 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.22 Å) |
Structure validation
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