Genetic and epigenetic control of the efficiency and fidelity of cross-species prion transmission

Abstract

SummarySelf-perpetuating amyloid-based protein isoforms (prions) transmit neurodegenerative diseases in mammals and phenotypic traits in yeast. Although mechanisms that control species specificity of prion transmission are poorly understood, studies of closely related orthologues of yeast prion protein Sup35 demonstrate that cross-species prion transmission is modulated by both genetic (specific sequence elements) and epigenetic (prion variants, or 'strains') factors. Depending on the prion variant, the species barrier could be controlled at the level of either heterologous co-aggregation or conversion of the aggregate-associated heterologous protein into a prion polymer. Sequence divergence influences cross-species transmission of different prion variants in opposing ways. The ability of a heterologous prion domain to either faithfully reproduce or irreversibly switch the variant-specific prion patterns depends on both sequence divergence and the prion variant. Sequence variations within different modules of prion domains contribute to transmission barriers in different cross-species combinations. Individual amino acid substitutions within short amyloidogenic stretches drastically alter patterns of cross-species prion conversion, implicating these stretches as major determinants of species specificity.

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

“…We generated and isolated a large series of [URE3] variants in a btn2Δ cur1Δ strain and restored normal levels of both Btn2p (41)(42)(43), the [URE3-bcs] variants expand the range of known possibilities of yeast prion characteristics. The [URE3-bcs] variants that we describe here would not be detected in a wild-type host, because they are rapidly eliminated by the combined action of Btn2p and Cur1p.…”

Ion-specific Effects on Prion Nucleation and Strain Formation

“…Given that amyloid formation is a site-specific, recognition-based process (23)(24)(25)(26)(27), such steric and/or electrostatic alterations likely hinder aggregation; however, resulting aggregates are characterized by higher order and more rigid structure. Apparently, the more robust amyloids form due to a selection pressure requiring a higher stringency of intermolecular interactions to overcome the anti-aggregation effect of chaotropic ions.…”

“…The high primary sequence specificity of amyloid propagation has been clearly demonstrated through mutational studies, construction of synthetic prion, and species barrier studies (23)(24)(25)(26)(27)(28). However, the mechanism of a curious phenomenon in prion biology where a given peptide can misfold into a variety of distinct amyloid structures, each leading to a distinct transmissible or inheritable phenotype (29 -31), remains unclear.…”

Prions in Yeast

“…Once a fiber forms with a set of b-sheets, steric zippers, and loops that represent a particular prion variant, new monomers that join the fiber are expected to be templated to form the same b-sheets, steric zippers, and loops ( Figure 7C). The inclusion of different PrD segments into different components of the structure may explain the different effects of specific PrD structural elements on Rnq1 prion propagation (Bardill and True 2009;Kadnar et al 2010) (see Prion domains) and on the specificity of [PSI + ] prion transmission (Chen et al 2010) (see below, Sequence Specificity of Prion Transmission and Transmission Barriers). One concern with the solid-state NMR data are that the widths of the lines (each of which represent an atom in a particular environment in the aggregates) of the Sup35, Rnq1, and Ure2 PrD spectra were much broader than expected.…”

“…This is similar to the range of variation observed for vertebrate prion proteins. Both complete Sup35 proteins and chimeric constructs with a heterologous PrD region were studied (Chen et al 2007(Chen et al , 2010Afanasieva et al 2011; see also Bruce and Chernoff 2011). SUP35 genes of different origins (or chimeric genes) were substituted for S. cerevisiae SUP35 by plasmid shuffle in a [PSI + ] S. cerevisiae cell.…”