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dc.contributor.author
Mulvihill, Estefania
dc.contributor.author
Sborgi, Lorenzo
dc.contributor.author
Mari, Stefania A.
dc.contributor.author
Pfreundschuh, Moritz
dc.contributor.author
Hiller, Sebastian
dc.contributor.author
Müller, Daniel J.
dc.date.accessioned
2018-07-27T12:27:31Z
dc.date.available
2018-07-27T06:56:17Z
dc.date.available
2018-07-27T12:27:31Z
dc.date.issued
2018-07-13
dc.identifier.other
10.15252/embj.201798321
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/278726
dc.identifier.doi
10.3929/ethz-b-000278726
dc.description.abstract
Gasdermin‐D (GSDMD), a member of the gasdermin protein family, mediates pyroptosis in human and murine cells. Cleaved by inflammatory caspases, GSDMD inserts its N‐terminal domain (GSDMDNterm) into cellular membranes and assembles large oligomeric complexes permeabilizing the membrane. So far, the mechanisms of GSDMDNterm insertion, oligomerization, and pore formation are poorly understood. Here, we apply high‐resolution (≤ 2 nm) atomic force microscopy (AFM) to describe how GSDMDNterm inserts and assembles in membranes. We observe GSDMDNterm inserting into a variety of lipid compositions, among which phosphatidylinositide (PI(4,5)P2) increases and cholesterol reduces insertion. Once inserted, GSDMDNterm assembles arc‐, slit‐, and ring‐shaped oligomers, each of which being able to form transmembrane pores. This assembly and pore formation process is independent on whether GSDMD has been cleaved by caspase‐1, caspase‐4, or caspase‐5. Using time‐lapse AFM, we monitor how GSDMDNterm assembles into arc‐shaped oligomers that can transform into larger slit‐shaped and finally into stable ring‐shaped oligomers. Our observations translate into a mechanistic model of GSDMDNterm transmembrane pore assembly, which is likely shared within the gasdermin protein family.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Wiley
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
cell death
en_US
dc.subject
inflammation
en_US
dc.subject
gasdermin-D pore assembly
en_US
dc.subject
time-lapse high-resolution atomic force microscopy
en_US
dc.subject
transmission electron microscopy
en_US
dc.title
Mechanism of membrane pore formation by human gasdermin-D
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2018-06-13
ethz.journal.title
EMBO Journal
ethz.journal.volume
37
en_US
ethz.journal.issue
14
en_US
ethz.pages.start
e98321
en_US
ethz.size
11 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Gleichzeitiges hochauflösendes Abbilden von Membranproteinen und dreidimensionales Kartieren der Wechselwirkungskräfte und Energielandschaften mit Liganden
en_US
ethz.identifier.scopus
ethz.publication.place
Weinheim
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03870 - Müller, Daniel J. / Müller, Daniel J.
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03870 - Müller, Daniel J. / Müller, Daniel J.
ethz.grant.agreementno
160199
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
ethz.date.deposited
2018-07-27T06:56:18Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-07-27T12:27:39Z
ethz.rosetta.lastUpdated
2019-01-02T13:30:43Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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