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Cryo-EM structure of the gasdermin A3 membrane pore

Author

Listed:
  • Jianbin Ruan

    (Boston Children’s Hospital
    Harvard Medical School)

  • Shiyu Xia

    (Boston Children’s Hospital
    Harvard Medical School)

  • Xing Liu

    (Boston Children’s Hospital
    Harvard Medical School)

  • Judy Lieberman

    (Boston Children’s Hospital
    Harvard Medical School)

  • Hao Wu

    (Boston Children’s Hospital
    Harvard Medical School)

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.

Suggested Citation

  • Jianbin Ruan & Shiyu Xia & Xing Liu & Judy Lieberman & Hao Wu, 2018. "Cryo-EM structure of the gasdermin A3 membrane pore," Nature, Nature, vol. 557(7703), pages 62-67, May.
    • Handle: RePEc:nat:nature:v:557:y:2018:i:7703:d:10.1038_s41586-018-0058-6
    DOI: 10.1038/s41586-018-0058-6
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    Cited by:

    1. Lisa D. J. Schiffelers & Yonas M. Tesfamariam & Lea-Marie Jenster & Stefan Diehl & Sophie C. Binder & Sabine Normann & Jonathan Mayr & Steffen Pritzl & Elena Hagelauer & Anja Kopp & Assaf Alon & Matth, 2024. "Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Stefania A. Mari & Kristyna Pluhackova & Joka Pipercevic & Matthew Leipner & Sebastian Hiller & Andreas Engel & Daniel J. Müller, 2022. "Gasdermin-A3 pore formation propagates along variable pathways," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Hang Yin & Jian Zheng & Qiuqiu He & Xuan Zhang & Xuzichao Li & Yongjian Ma & Xiao Liang & Jiaqi Gao & Benjamin L. Kocsis & Zhuang Li & Xiang Liu & Neal M. Alto & Long Li & Heng Zhang, 2023. "Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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