title: Functional amyloidogenesis and cytotoxicity-insights into biology and pathology.
abstract: Prions are self-templating protein structures that can be transferred from organism to organism. The [Het-s] prion propagates as a functional amyloid aggregate in the filamentous fungi Podospora anserina, and is involved in mediating heterokaryon incompatibility. Fusion of a P. anserina strain harboring the [Het-s] prion with another strain expressing the soluble Het-S protein results in cell death. The mechanism of Het-s/Het-S-mediated cell death has now been revealed in a paper just published in PLOS Biology. The study shows that Het-s and Het-S C-terminal domain co-amyloidogenesis induces a profound conformational rearrangement in the N-terminal Het-S HeLo domain, resulting in the exposure of a nascent transmembrane helix. Oligomerization of these helices leads to pore formation, leakage of the cytosolic contents, and subsequent cell death. Thus, Het-s amyloid plays a major role in the life cycle of P. anserina by orchestrating a complex conformational change in the Het-S protein, resulting in cytotoxicity by compromising membrane integrity. This ability of Het-s functional amyloid to initiate programmed cytotoxicity by mediating a conformational change in another protein significantly expands the functional repertoire of amyloid. Moreover, the mechanism of Het-S cell killing may be similar to the mechanism by which some pathological amyloid proteins lead to the demise of post-mitotic tissue.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA. dfowler@uw.edu
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Fowler
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004194:Disease; D005656:Fungal Proteins / Q000633:toxicity; D006262:Health; D006801:Humans; D009183:Mycotoxins / Q000633:toxicity; D048468:Podospora / Q000502:physiology; D011328:Prions / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; C083891:HET-S protein, Podospora anserina; D009183:Mycotoxins; D011328:Prions