The yeast prion Ure2p native-like assemblies are toxic to mammalian cells regardless to their aggregation state

doi:10.1074/jbc.M511647200

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Papers In Press, published online ahead of print March 29, 2006
J. Biol. Chem, 10.1074/jbc.M511647200
Submitted on October 27, 2005
Accepted on March 29, 2006

The yeast prion Ure2p native-like assemblies are toxic to mammalian cells regardless to their aggregation state

Laura Pieri, Monica Bucciantini, Daniele Nosi, Lucia Formigli, Jimmy Savistchenko, Ronald Melki, and Massimo Stefani

Biochemical Sciences, University of Florence, Florence 50134

Corresponding Author: stefani{at}scibio.unifi.it

The yeast prion Ure2p assembles in vitro into oligomers and fibrils retaining the a-helix content and binding properties of the soluble protein. Here we show that the different forms of Ure2p native-like assemblies (dimers, oligomers and fibrils) are similarly toxic to murine H-END cells when added to the culture medium. Interestingly, the amyloid fibrils obtained by heat treatment of the toxic native-like fibrils appear harmless. Moreover, the Ure2p C-terminal domain, lacking the N-terminal segment necessary for aggregation, but containing the glutathione binding site, is not cytotoxic. This finding strongly supports the idea that Ure2p toxicity depends on the structural properties of the flexible N-terminal prion domain and can therefore be considered as an inherent feature of the protein, unrelated to its aggregation state, but rather associated with a basic toxic fold shared by all the Ure2p native-like assemblies. Indeed, the latter are able to interact with the cell surface leading to alteration of calcium homeostasis, membrane permeabilization and oxidative stress, whereas the heat-treated amyloid fibrils do not. Our results support the idea of a general mechanism of toxicity of any protein/peptide aggregate endowed with structural features making it able to interact with cell membranes and to destabilize them. These evidences extend the widely accepted view that the toxicity by protein aggregates is restricted to amyloid prefibrillar aggregates and provide new insights into the mechanism by which native-like oligomers compromise cell viability.

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