The mechanism of toxicity in HET-S/HET-s prion incompatibility.
The HET-s protein from the filamentous fungus Podospora anserina is a prion involved in a cell death reaction termed heterokaryon incompatibility. This reaction is observed at the point of contact between two genetically distinct strains when one harbors a HET-s prion (in the form of amyloid aggrega...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23300377/pdf/?tool=EBI |
| _version_ | 1818700987590770688 |
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| author | Carolin Seuring Jason Greenwald Christian Wasmer Roger Wepf Sven J Saupe Beat H Meier Roland Riek |
| author_facet | Carolin Seuring Jason Greenwald Christian Wasmer Roger Wepf Sven J Saupe Beat H Meier Roland Riek |
| author_sort | Carolin Seuring |
| collection | DOAJ |
| description | The HET-s protein from the filamentous fungus Podospora anserina is a prion involved in a cell death reaction termed heterokaryon incompatibility. This reaction is observed at the point of contact between two genetically distinct strains when one harbors a HET-s prion (in the form of amyloid aggregates) and the other expresses a soluble HET-S protein (96% identical to HET-s). How the HET-s prion interaction with HET-S brings about cell death remains unknown; however, it was recently shown that this interaction leads to a relocalization of HET-S from the cytoplasm to the cell periphery and that this change is associated with cell death. Here, we present detailed insights into this mechanism in which a non-toxic HET-s prion converts a soluble HET-S protein into an integral membrane protein that destabilizes membranes. We observed liposomal membrane defects of approximately 10 up to 60 nm in size in transmission electron microscopy images of freeze-fractured proteoliposomes that were formed in mixtures of HET-S and HET-s amyloids. In liposome leakage assays, HET-S has an innate ability to associate with and disrupt lipid membranes and that this activity is greatly enhanced when HET-S is exposed to HET-s amyloids. Solid-state nuclear magnetic resonance (NMR) analyses revealed that HET-s induces the prion-forming domain of HET-S to adopt the β-solenoid fold (previously observed in HET-s) and this change disrupts the globular HeLo domain. These data indicate that upon interaction with a HET-s prion, the HET-S HeLo domain partially unfolds, thereby exposing a previously buried ∼34-residue N-terminal transmembrane segment. The liberation of this segment targets HET-S to the membrane where it further oligomerizes, leading to a loss of membrane integrity. HET-S thus appears to display features that are reminiscent of pore-forming toxins. |
| first_indexed | 2024-12-17T15:13:41Z |
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| id | doaj.art-4d95b330bb97425cb7b5d1d55a63b52a |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-17T15:13:41Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-4d95b330bb97425cb7b5d1d55a63b52a2022-12-21T21:43:35ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852012-01-011012e100145110.1371/journal.pbio.1001451The mechanism of toxicity in HET-S/HET-s prion incompatibility.Carolin SeuringJason GreenwaldChristian WasmerRoger WepfSven J SaupeBeat H MeierRoland RiekThe HET-s protein from the filamentous fungus Podospora anserina is a prion involved in a cell death reaction termed heterokaryon incompatibility. This reaction is observed at the point of contact between two genetically distinct strains when one harbors a HET-s prion (in the form of amyloid aggregates) and the other expresses a soluble HET-S protein (96% identical to HET-s). How the HET-s prion interaction with HET-S brings about cell death remains unknown; however, it was recently shown that this interaction leads to a relocalization of HET-S from the cytoplasm to the cell periphery and that this change is associated with cell death. Here, we present detailed insights into this mechanism in which a non-toxic HET-s prion converts a soluble HET-S protein into an integral membrane protein that destabilizes membranes. We observed liposomal membrane defects of approximately 10 up to 60 nm in size in transmission electron microscopy images of freeze-fractured proteoliposomes that were formed in mixtures of HET-S and HET-s amyloids. In liposome leakage assays, HET-S has an innate ability to associate with and disrupt lipid membranes and that this activity is greatly enhanced when HET-S is exposed to HET-s amyloids. Solid-state nuclear magnetic resonance (NMR) analyses revealed that HET-s induces the prion-forming domain of HET-S to adopt the β-solenoid fold (previously observed in HET-s) and this change disrupts the globular HeLo domain. These data indicate that upon interaction with a HET-s prion, the HET-S HeLo domain partially unfolds, thereby exposing a previously buried ∼34-residue N-terminal transmembrane segment. The liberation of this segment targets HET-S to the membrane where it further oligomerizes, leading to a loss of membrane integrity. HET-S thus appears to display features that are reminiscent of pore-forming toxins.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23300377/pdf/?tool=EBI |
| spellingShingle | Carolin Seuring Jason Greenwald Christian Wasmer Roger Wepf Sven J Saupe Beat H Meier Roland Riek The mechanism of toxicity in HET-S/HET-s prion incompatibility. PLoS Biology |
| title | The mechanism of toxicity in HET-S/HET-s prion incompatibility. |
| title_full | The mechanism of toxicity in HET-S/HET-s prion incompatibility. |
| title_fullStr | The mechanism of toxicity in HET-S/HET-s prion incompatibility. |
| title_full_unstemmed | The mechanism of toxicity in HET-S/HET-s prion incompatibility. |
| title_short | The mechanism of toxicity in HET-S/HET-s prion incompatibility. |
| title_sort | mechanism of toxicity in het s het s prion incompatibility |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23300377/pdf/?tool=EBI |
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