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Gasdermin-A3 pore formation propagates along variable pathways

Author

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  • Stefania A. Mari

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Kristyna Pluhackova

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Joka Pipercevic

    (Biozentrum, University of Basel)

  • Matthew Leipner

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Sebastian Hiller

    (Biozentrum, University of Basel)

  • Andreas Engel

    (Eidgenössische Technische Hochschule (ETH) Zurich)

  • Daniel J. Müller

    (Eidgenössische Technische Hochschule (ETH) Zurich)

Abstract

Gasdermins are main effectors of pyroptosis, an inflammatory form of cell death. Released by proteolysis, the N-terminal gasdermin domain assembles large oligomers to punch lytic pores into the cell membrane. While the endpoint of this reaction, the fully formed pore, has been well characterized, the assembly and pore-forming mechanisms remain largely unknown. To resolve these mechanisms, we characterize mouse gasdermin-A3 by high-resolution time-lapse atomic force microscopy. We find that gasdermin-A3 oligomers assemble on the membrane surface where they remain attached and mobile. Once inserted into the membrane gasdermin-A3 grows variable oligomeric stoichiometries and shapes, each able to open transmembrane pores. Molecular dynamics simulations resolve how the membrane-inserted amphiphilic β-hairpins and the structurally adapting hydrophilic head domains stabilize variable oligomeric conformations and open the pore. The results show that without a vertical collapse gasdermin pore formation propagates along a set of multiple parallel but connected reaction pathways to ensure a robust cellular response.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30232-8
    DOI: 10.1038/s41467-022-30232-8
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    References listed on IDEAS

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