Sublytic gasdermin-D pores captured in atomistic molecular simulations
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 formatio...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/81432 |
| _version_ | 1811304790797320192 |
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| author | Stefan L Schaefer Gerhard Hummer |
| author_facet | Stefan L Schaefer Gerhard Hummer |
| author_sort | Stefan L Schaefer |
| collection | DOAJ |
| description | 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 atomic force microscopy experiments. 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. |
| first_indexed | 2024-04-13T08:13:26Z |
| format | Article |
| id | doaj.art-3a3c946fa12a4f72b2c92b82df8b83b1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T08:13:26Z |
| publishDate | 2022-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3a3c946fa12a4f72b2c92b82df8b83b12022-12-22T02:54:52ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.81432Sublytic gasdermin-D pores captured in atomistic molecular simulationsStefan L Schaefer0https://orcid.org/0000-0001-7942-8701Gerhard Hummer1https://orcid.org/0000-0001-7768-746XDepartment of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, GermanyDepartment of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany; Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, GermanyGasdermin-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 atomic force microscopy experiments. 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.https://elifesciences.org/articles/81432pyroptosisgasderminGSDMDPI(4,5)P2 bindingmembrane edge tensionpore forming protein |
| spellingShingle | Stefan L Schaefer Gerhard Hummer Sublytic gasdermin-D pores captured in atomistic molecular simulations eLife pyroptosis gasdermin GSDMD PI(4,5)P2 binding membrane edge tension pore forming protein |
| title | Sublytic gasdermin-D pores captured in atomistic molecular simulations |
| title_full | Sublytic gasdermin-D pores captured in atomistic molecular simulations |
| title_fullStr | Sublytic gasdermin-D pores captured in atomistic molecular simulations |
| title_full_unstemmed | Sublytic gasdermin-D pores captured in atomistic molecular simulations |
| title_short | Sublytic gasdermin-D pores captured in atomistic molecular simulations |
| title_sort | sublytic gasdermin d pores captured in atomistic molecular simulations |
| topic | pyroptosis gasdermin GSDMD PI(4,5)P2 binding membrane edge tension pore forming protein |
| url | https://elifesciences.org/articles/81432 |
| work_keys_str_mv | AT stefanlschaefer sublyticgasdermindporescapturedinatomisticmolecularsimulations AT gerhardhummer sublyticgasdermindporescapturedinatomisticmolecularsimulations |