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Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr 25.

Cryo-EM structure of the gasdermin A3 membrane pore.

Ruan J1,2, Xia S1,2, Liu X1,3, Lieberman J1,3, Wu H4,5.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3
Department of Paediatrics, Harvard Medical School, Boston, MA, USA.
4
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. wu@crystal.harvard.edu.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. wu@crystal.harvard.edu.

Abstract

Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of pore formation remains unresolved. Here we present the cryo-electron microscopy structures of the 27-fold and 28-fold single-ring pores formed by the N-terminal fragment of mouse GSDMA3 (GSDMA3-NT) at 3.8 and 4.2 Å resolutions, and of a double-ring pore at 4.6 Å resolution. In the 27-fold pore, a 108-stranded anti-parallel β-barrel is formed by two β-hairpins from each subunit capped by a globular domain. We identify a positively charged helix that interacts with the acidic lipid cardiolipin. GSDMA3-NT undergoes radical conformational changes upon membrane insertion to form long, membrane-spanning β-strands. We also observe an unexpected additional symmetric ring of GSDMA3-NT subunits that does not insert into the membrane in the double-ring pore, which may represent a pre-pore state of GSDMA3-NT. These structures provide a basis that explains the activities of several mutant gasdermins, including defective mutants that are associated with cancer.

PMID:
29695864
PMCID:
PMC6007975
DOI:
10.1038/s41586-018-0058-6
[Indexed for MEDLINE]
Free PMC Article

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