Sublytic gasdermin-D pores captured in atomistic molecular simulations

  1. Stefan L Schaefer
  2. Gerhard Hummer  Is a corresponding author
  1. Max Planck Institute of Biophysics, Germany

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.

Data availability

The data in this study are included in the manuscript and source data files.

Article and author information

Author details

  1. Stefan L Schaefer

    Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7942-8701
  2. Gerhard Hummer

    Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
    For correspondence
    gerhard.hummer@biophys.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7768-746X

Funding

Deutsche Forschungsgemeinschaft (CRC 1507)

  • Stefan L Schaefer
  • Gerhard Hummer

Max-Planck-Gesellschaft

  • Stefan L Schaefer
  • Gerhard Hummer

Hessisches Ministerium für Wissenschaft und Kunst (Cluster project ENABLE)

  • Stefan L Schaefer
  • Gerhard Hummer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. José D Faraldo-Gómez, National Institutes of Health, United States

Version history

  1. Preprint posted: June 3, 2022 (view preprint)
  2. Received: June 27, 2022
  3. Accepted: November 11, 2022
  4. Accepted Manuscript published: November 14, 2022 (version 1)
  5. Version of Record published: November 25, 2022 (version 2)

Copyright

© 2022, Schaefer & Hummer

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Stefan L Schaefer
  2. Gerhard Hummer
(2022)
Sublytic gasdermin-D pores captured in atomistic molecular simulations
eLife 11:e81432.
https://doi.org/10.7554/eLife.81432

Share this article

https://doi.org/10.7554/eLife.81432

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