10.1371/journal.pbio.1001451
Carolin Seuring
Carolin
Seuring
Jason Greenwald
Jason
Greenwald
Christian Wasmer
Christian
Wasmer
Roger Wepf
Roger
Wepf
Sven J. Saupe
Sven
J. Saupe
Beat H. Meier
Beat H.
Meier
Roland Riek
Roland
Riek
The Mechanism of Toxicity in HET-S/HET-s Prion Incompatibility
Public Library of Science
2012
toxicity
prion
incompatibility
2012-12-27 01:28:19
Dataset
https://plos.figshare.com/articles/dataset/The_Mechanism_of_Toxicity_in_HET_S_HET_s_Prion_Incompatibility__/115299
<div><p>The HET-s protein from the filamentous fungus <em>Podospora anserina</em> 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.</p> </div>