Gasdermin-A3 pore formation propagates along variable pathways

Stefania A. Mari, Kristyna Pluhackova (), Joka Pipercevic, Matthew Leipner, Sebastian Hiller, Andreas Engel and Daniel J. Müller ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-30232-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30232-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-30232-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().