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1.C.104 The Heterokaryon Incompatibility Prion/Amyloid Protein (HET-s) Family

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, this interaction leads to a relocalization of HET-S from the cytoplasm to the cell periphery, and this change is associated with cell death. A non-toxic HET-s prion converts a soluble HET-S protein into an integral membrane protein that destabilizes membranes (Seuring et al. 2012). Liposomal membrane defects of approximately 10 up to 60 nm in size in transmission electron microscopy images of freeze-fractured proteoliposomes 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 this activity is greatly enhanced when HET-S is exposed to HET-s amyloids. 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. Thus, upon interaction with a HET-s prion, the HET-S HeLo domain partially unfolds, 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 displays features that are reminiscent of pore-forming toxins (Seuring et al., 2012).

References associated with 1.C.104 family:

Seuring, C., J. Greenwald, C. Wasmer, R. Wepf, S.J. Saupe, B.H. Meier, and R. Riek. (2012). The mechanism of toxicity in HET-S/HET-s prion incompatibility. PLoS Biol 10: e1001451. 23300377