Heterologous cross-seeding mimics cross-species prion conversion in a yeast model.
BACKGROUND
Prions are self-perpetuating, infectious, aggregated proteins that are associated with several neurodegenerative diseases in mammals and heritable traits in yeast. Sup35p, the protein determinant of the yeast prion [PSI+], has a conserved C terminal domain that performs the Sup35p function and a prion domain that is highly divergent. Prions formed by chimeras of the prion domain of various species fused to the C domain of Saccharomyces cerevisiae exhibit a 'species barrier', a phenomenon first observed in mammals, and often fail to transmit the prion state to chimeras with prion domains of other species.


RESULTS
We focus on the chimera containing the prion domain of Pichia methanolica and examine how tight the 'species barrier' is between the chimera and S. cerevisiae. Although either of two Q/N-rich prions, [PSI+] or [PIN+], enhances the formation of the chimeric prion, [CHI+PM], neither a non-Q/N-rich prion nor a non-prion Q-rich aggregate promotes the formation of [CHI+PM]. [CHI+PM] has many features characteristic of yeast prions: aggregation, cytoplasmic transmission and a two-level protein structure. [CHI+PM] formed in the presence of [PSI+] can propagate independently of [PSI+] and forms at least two different variants of the prion, suggesting the generation and not transmission of new prion seeds.


CONCLUSIONS
Although the sequence similarity between the S. cerevisiae Q/N-rich prion determinants and the P. methanolica prion domain is low, we find that the chimera containing the prion domain of P. methanolica can occasionally be cross-seeded by [PSI+] to mimic crossing the species barrier, to form the [CHI+PM] prion. Our data suggests that crossing the barrier occurs by a de novo formation of the foreign chimeric prion. Thus, the species barrier appears to be crossed by a heterologous seeding mechanism, wherein the infected prion protein uses the pre-existing seed as an inefficient template.
Vishveshwara
Namitha
N
Department of Biological Sciences, Chicago, IL 60607, USA. namivish@yahoo.com
Liebman
Susan W
SW
D015169:Colony Count, Microbial; D008954:Models, Biological; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000235:genetics; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D013045:Species Specificity
D010455:Peptides; D011328:Prions; C097188:polyglutamine