Gasdermin-A3 pore formation propagates along variable pathways.

Autor: Mari SA; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058, Basel, Switzerland., Pluhackova K; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058, Basel, Switzerland. kristyna.pluhackova@bsse.ethz.ch., Pipercevic J; Biozentrum, University of Basel, 4056, Basel, Switzerland., Leipner M; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058, Basel, Switzerland., Hiller S; Biozentrum, University of Basel, 4056, Basel, Switzerland., Engel A; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058, Basel, Switzerland., Müller DJ; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058, Basel, Switzerland. daniel.mueller@bsse.ethz.ch.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 May 11; Vol. 13 (1), pp. 2609. Date of Electronic Publication: 2022 May 11.
DOI: 10.1038/s41467-022-30232-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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