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Strain conformation, primary structure and the propagation of the yeast prion [PSI+].

ABSTRACT: Prion proteins can adopt multiple infectious strain conformations. Here we investigate how the sequence of a prion protein affects its capacity to propagate specific conformations by exploiting our ability to create two distinct infectious conformations of the yeast [PSI(+)] prion protein Sup35, termed Sc4 and Sc37. PNM2, a G58D point mutant of Sup35 that was originally identified for its dominant interference with prion propagation, leads to rapid, recessive loss of Sc4 but does not interfere with propagation of Sc37. PNM2 destabilizes the amyloid core of Sc37 and causes compensatory effects that slow prion growth but aid prion division and result in robust propagation of Sc37. By contrast, PNM2 does not affect the structure or chaperone-mediated division of Sc4 but interferes with its delivery to daughter cells. Thus, effective delivery of infectious particles during cell division is a crucial and conformation-dependent step in prion inheritance.

SUBMITTER: Verges KJ

PROVIDER: S-EPMC3490428 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

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Strain conformation, primary structure and the propagation of the yeast prion [PSI+].

Verges Katherine J KJ Smith Melanie H MH Toyama Brandon H BH Weissman Jonathan S JS

Nature structural & molecular biology 20110320 4

Prion proteins can adopt multiple infectious strain conformations. Here we investigate how the sequence of a prion protein affects its capacity to propagate specific conformations by exploiting our ability to create two distinct infectious conformations of the yeast [PSI(+)] prion protein Sup35, termed Sc4 and Sc37. PNM2, a G58D point mutant of Sup35 that was originally identified for its dominant interference with prion propagation, leads to rapid, recessive loss of Sc4 but does not interfere w ...[more]

PMID: 21423194

Similar Datasets

Strain-specific sequences required for yeast [PSI+] prion propagation.

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| S-EPMC2533192 | biostudies-literature

Structural definition is important for the propagation of the yeast [PSI+] prion.

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Molecular basis for diversification of yeast prion strain conformation.

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[PSI+] prion propagation is controlled by inositol polyphosphates.

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[PSI(+) ] prion variant establishment in yeast.

Project description:Differences in the clinical pathology of mammalian prion diseases reflect distinct heritable conformations of aggregated PrP proteins, called prion strains. Here, using the yeast [PSI(+) ] prion, we examine the de novo establishment of prion strains (called variants in yeast). The [PSI(+) ] prion protein, Sup35, is efficiently induced to take on numerous prion variant conformations following transient overexpression of Sup35 in the presence of another prion, e.g. [PIN(+) ]. One hypothesis is that the first [PSI(+) ] prion seed to arise in a cell causes propagation of only that seed's variant, but that different variants could be initiated in different cells. However, we now show that even within a single cell, Sup35 retains the potential to fold into more than one variant type. When individual cells segregating different [PSI(+) ] variants were followed in pedigrees, establishment of a single variant phenotype generally occurred in daughters, granddaughters or great-granddaughters - but in 5% of the pedigrees cells continued to segregate multiple variants indefinitely. The data are consistent with the idea that many newly formed prions go through a maturation phase before they reach a single specific variant conformation. These findings may be relevant to mammalian PrP prion strain establishment and adaptation.

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| S-EPMC5082969 | biostudies-literature

Inter-allelic prion propagation reveals conformational relationships among a multitude of [PSI] strains.

Project description:Immense diversity of prion strains is observed, but its underlying mechanism is less clear. Three [PSI] prion strains--named VH, VK, and VL--were previously isolated in the wild-type yeast genetic background. Here we report the generation and characterization of eight new [PSI] isolates, obtained by propagating the wild-type strains with Sup35 proteins containing single amino-acid alterations. The VH strain splits into two distinct strains when propagated in each of the three genetic backgrounds, harboring respectively single mutations of N21L, R28P, and Gi47 (i.e. insertion of a glycine residue at position 47) on the Sup35 N-terminal prion-forming segment. The six new strains exhibit complex inter-conversion patterns, and one of them continuously mutates into another. However, when they are introduced back into the wild-type background, all 6 strains revert to the VH strain. We obtain two more [PSI] isolates by propagating VK and VL with the Gi47 and N21L backgrounds, respectively. The two isolates do not transmit to other mutant backgrounds but revert to their parental strains in the wild-type background. Our data indicate that a large number of [PSI] strains can be built on three basic Sup35 amyloid structures. It is proposed that the three basic structures differ by chain folding topologies, and sub-strains with the same topology differ in distinct ways by local structural adjustments. This "large number of variations on a small number of basic themes" may also be operative in generating strain diversities in other prion elements. It thus suggests a possible general scheme to classify a multitude of prion strains.

| S-EPMC3183073 | biostudies-literature

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