Abstract
Prions of lower eukaryotes are self-templating protein aggregates that replicate by converting homotypic proteins into stable, tightly packed beta-sheet-rich protein assemblies. Propagation is mediated by prion domains, low-complexity regions enriched in polar and devoid of charged amino acid residues. In mammals, compositionally similar domains modulate the assembly of dynamic stress granules (SGs) that associate via multivalent weak interactions. Dysregulation of SGs composed of proteins with prion-like domains has been proposed to underlie the formation of pathological inclusions in several neurodegenerative diseases. The events that drive prion-like domains into transient or solid assemblies are not well understood. We studied the interactors of the prototype prion domain NM of Saccharomyces cerevisiae Sup35 in its soluble or fibril-induced prion conformation in the mammalian cytosol. We show that the interactomes of soluble and prionized NM overlap with that of SGs. Prion induction by exogenous seeds does not cause SG assembly, demonstrating that colocalization of aberrant protein inclusions with SG components does not necessarily reveal SGs as initial sites of protein misfolding.
Highlights
Prions of yeast and filamentous fungi constitute self-replicating entities composed of higher-order protein polymers
We studied the interaction network of the archetypical lowcomplexity Q/N-rich prion domain derived from the yeast Sup35 prion protein that lacks specific physiological function in mammalian cells
We demonstrate that the interactomes of both soluble and insoluble NM are highly enriched for intrinsically disordered proteins and RNA-binding proteins
Summary
Prions of yeast and filamentous fungi constitute self-replicating entities composed of higher-order protein polymers. Yeast prion induction is a rare event that can be triggered in response to environmental changes. The translation termination factor Sup, composed of the domains N, M, and C, represents the best-studied prion of Saccharomyces cerevisiae (King et al, 1997). Adoption of the prion conformation is a rare event and renders Sup inactive, resulting in translational readthrough and a change in metabolic phenotype. Conversion of Sup into the prion conformation can be templated by recombinant NM amyloid fibrils (King et al, 2006; Tanaka et al, 2006). The Sup N and M domains mediate the switch between the soluble functional and the insoluble prion state. The charged middle domain M helps to keep the protein in its monomeric state (Glover et al, 1997), whereas the carboxyterminal C domain governs catalytic activity and is otherwise dispensable for prion formation (Glover et al, 1997)
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