Cryo-EM structure of the gasdermin A3 membrane pore

Jianbin Ruan, Shiyu Xia, Xing Liu, Judy Lieberman and Hao Wu ()
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Jianbin Ruan: Boston Children’s Hospital
Shiyu Xia: Boston Children’s Hospital
Xing Liu: Boston Children’s Hospital
Judy Lieberman: Boston Children’s Hospital
Hao Wu: Boston Children’s Hospital

Nature, 2018, vol. 557, issue 7703, 62-67

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0058-6

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