Functional Amyloidogenesis and Cytotoxicity—Insights into Biology and Pathology |
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Authors: | Douglas M Fowler Jeffery W Kelly |
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Institution: | 1.Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America;2.Department of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America;3.Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America;4.Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America |
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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. |
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