Functional Amyloidogenesis and Cytotoxicity-Insights into Biology and Pathology

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. © 2012 fowler,kelly.