Prions of lower eukaryotes are self-templating protein aggregates with cores formed by parallel in-register beta strands. Short aggregation-prone glutamine (Q)- and asparagine (N)-rich regions embedded in longer disordered domains have been proposed to act as nucleation sites that initiate refolding of soluble prion proteins into highly ordered fibrils, termed amyloid. We demonstrate that a short Q/N-rich peptide corresponding to a proposed nucleation site in the prototype Saccharomyces cerevisiae prion protein Sup35 is sufficient to induce infectious cytosolic prions in mouse neuroblastoma cells ectopically expressing the soluble Sup35 NM prion domain. Embedding this nucleating core in a non-native N-rich sequence that does not form amyloid but acts as an entropic bristle quadruples seeding efficiency. Our data suggest that large disordered sequences flanking an aggregation core in prion proteins act as not only solubilizers of the monomeric protein but also breakers of the formed amyloid fibrils, enhancing infectivity of the prion seeds.

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Journal Article | Research Support, Non-U.S. Gov't

Authors

Michiels E, Liu S, Gallardo R, Louros N, Mathelié-Guinlet M, Dufrêne Y, Schymkowitz J, Vorberg I, Rousseau F

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