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  Sublytic gasdermin-D pores captured in atomistic molecular simulations

Schaefer, S. L., & Hummer, G. (2022). Sublytic gasdermin-D pores captured in atomistic molecular simulations. eLife, 11: e81432. doi:10.7554/eLife.81432.

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 Creators:
Schaefer, Stefan L.1, Author                 
Hummer, Gerhard1, 2, Author                 
Affiliations:
1Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
2Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany, ou_persistent22              

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 Abstract: Gasdermin-D (GSDMD) is the ultimate effector of pyroptosis, a form of programmed cell death associated with pathogen invasion and inflammation. After proteolytic cleavage by caspases, the GSDMD N-terminal domain (GSDMDNT) assembles on the inner leaflet of the plasma membrane and induces the formation of membrane pores. We use atomistic molecular dynamics simulations to study GSDMDNT monomers, oligomers, and rings in an asymmetric plasma membrane mimetic. We identify distinct interaction motifs of GSDMDNT with phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and phosphatidylserine (PS) headgroups and describe their conformational dependence. Oligomers are stabilized by shared lipid binding sites between neighboring monomers acting akin to double-sided tape. We show that already small GSDMDNT oligomers support stable, water-filled and ion-conducting membrane pores bounded by curled beta-sheets. In large-scale simulations, we resolve the process of pore formation from GSDMDNT arcs and lipid efflux from partial rings. We find that high-order GSDMDNT oligomers can crack under the line tension of 86 pN created by an open membrane edge to form the slit pores or closed GSDMDNT rings seen in experiment. Our simulations provide a detailed view of key steps in GSDMDNT-induced plasma membrane pore formation, including sublytic pores that explain nonselective ion flux during early pyroptosis.

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Language(s): eng - English
 Dates: 2022-11-14
 Publication Status: Published online
 Pages: 23
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.7554/eLife.81432
BibTex Citekey: schaefer_sublytic_2022
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Title: eLife
Source Genre: Journal
 Creator(s):
Faraldo-Gómez, José D, Editor
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Publ. Info: Cambridge : eLife Sciences Publications
Pages: - Volume / Issue: 11 Sequence Number: e81432 Start / End Page: - Identifier: Other: URL
ISSN: 2050-084X
CoNE: https://pure.mpg.de/cone/journals/resource/2050-084X