Mechanism of membrane pore formation by human gasdermin-D

Mulvihill, Estefania and Sborgi, Lorenzo and Mari, Stefania A. and Pfreundschuh, Moritz and Hiller, Sebastian and Müller, Daniel J.. (2018) Mechanism of membrane pore formation by human gasdermin-D. The EMBO journal, 37 (14). e98321.

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Official URL: https://edoc.unibas.ch/68411/

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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 (GSDMD; Nterm; ) into cellular membranes and assembles large oligomeric complexes permeabilizing the membrane. So far, the mechanisms of GSDMD; Nterm; insertion, oligomerization, and pore formation are poorly understood. Here, we apply high-resolution (≤ 2 nm) atomic force microscopy (AFM) to describe how GSDMD; Nterm; inserts and assembles in membranes. We observe GSDMD; Nterm; inserting into a variety of lipid compositions, among which phosphatidylinositide (PI(4,5)P2) increases and cholesterol reduces insertion. Once inserted, GSDMD; Nterm; 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 GSDMD; Nterm; 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 GSDMD; Nterm; transmembrane pore assembly, which is likely shared within the gasdermin protein family.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:EMBO Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Feb 2020 15:32
Deposited On:10 Feb 2020 15:32

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