Prion species barrier between the closely related yeast proteins is detected despite coaggregation

Abstract

Prions are self-perpetuating and, in most cases, aggregation-prone protein isoforms that transmit neurodegenerative diseases in mammals and control heritable traits in yeast. Prion conversion requires a very high level of identity of the interacting protein sequences. Decreased transmission of the prion state between divergent proteins is termed ''species barrier'' and was thought to occur because of the inability of divergent prion proteins to coaggregate. Species barrier can be overcome in cross-species infections, e.g., from ''mad cows'' to humans. We studied the counterparts of yeast prion protein Sup35, originated from three different species of the Saccharomyces sensu stricto group and exhibiting the range of prion domain divergence that overlaps with the range of divergence observed among distant mammalian species. All three proteins were capable of forming a prion in Saccharomyces cerevisiae, although prions formed by heterologous proteins were usually less stable than the endogenous S. cerevisiae prion. Heterologous Sup35 proteins coaggregated in the S. cerevisiae cells. However, in vivo cross-species prion conversion was decreased and in vitro polymerization was cross-inhibited in at least some heterologous combinations, thus demonstrating the existence of prion species barrier. Moreover, the barrier between the S. cerevisiae protein and its Saccharomyces paradoxus and Saccharomyces bayanus counterparts was asymmetric both in vivo and in vitro. Our data show that a decreased cross-species prion transmission does not necessarily correlate with a lack of crossspecies coaggregation, suggesting that species-specificity of prion transmission is controlled at the level of conformational transition rather than coaggregation.amyloid ͉ Saccharomyces bayanus ͉ Saccharomyces cerevisiae ͉ Saccharomyces paradoxus ͉ Sup35

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.…”

Sex, prions, and plasmids in yeast

“…30), later recognized as a requirement for homozygosity at PrP residue 129 for Creutzfeldt-Jakob disease (31), and recently reported in a barrier to the transmission of [PSI+] and of [URE3] between Saccharomyces species (32,33). Even within S. cerevisiae, there are several groups of polymorphs of Sup35p between which prion transmission is inefficient; we suggest the existence of these polymorphs was selected to protect yeast from the detrimental effects of [PSI+] (34), just as polymorphisms of human PrP are believed to have been selected to protect against kuru-like epidemics of prion disease (31).…”

Sporadic Distribution of Prion-Forming Ability of Sup35p from Yeasts and Fungi

“…The sequence of the prion domains of Sup35p and Ure2p are not conserved and in fact show far more rapid variability in evolution than does the remainder of the molecules (Jensen et al 2001;Edskes and Wickner 2002;Baudin-Baillieu et al 2003;Bateman and Wickner 2012). The sequence changes produce barriers to transmission of [PSI+] within S. cerevisiae (Bateman and Wickner 2012), as well as between species for both prions (Chen et al 2007;). …”

“…Replacing the S. cerevisiae Sup35 NM or N domain with the corresponding Sup35p domain of Pichia methanolica (Chernoff et al 2000;Kushnirov et al 2000;Santoso et al 2000), S. paradoxus, S. bayanus, S. kudriavzevii, or S. mikatae produces fusion molecules that can form [PSI+] prions in S. cerevisiae (Chen et al 2007;Afanasieva et al 2011). Likewise, replacing the S. cerevisiae N domain with that of Kluyveromyces lactis or Candida albicans produced fusion proteins that showed prion-like behavior in S. cerevisiae (Santoso et al 2000).…”