Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae

Kathryn M. Keefer, Kevin C. Stein & Heather L. True: 2017 Scientific Reports 7, Article number: 5853 Read More


The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders. © 2017 The Author(s).

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Posted on August 14, 2017
Posted in: HPAN, Neurodegeneration, Publications Authors: