| Prions were originally described in mammals as the protein-based causative agent of the transmissible spongiform encephalopathies. Prions are defined by their ability to exist in an alternate conformation that facilitates other molecules to assume this conformation. The discovery of prions in Saccharomyces cerevisiae and other fungi has provided proof that a change in a protein's conformation is sufficient to induce phenotypic changes.;[PIN+], the prion form of Rnq1p, is common in wild and laboratory yeast strains where is facilitates the appearance of other prions. All aspects of the yeast prion cycle are dependent on its QN-rich prion domain. Rnq1p has a large prion domain with four discrete QN regions and is highly polymorphic in wild yeast. Using a series of Rnq1p prion domain deletion fragments. I show that the Rnq1p prion domain is redundant. This redundancy allows Rnq1p fragments to propagate as [PIN +fgmt], but not before crossing a transmission barrier to the acquisition of the prion state.;I then use the complexity of the Rnq1p prion domain to explore the nature of this transmission barrier. Transmission of the [PIN +] or [PIN+fgmt] state requires a common QN region between the prion protein and the soluble protein. However, when [PIN+fgmt]s are used to convert wildtype Rnq1p to [PIN+], a transmission barrier is still present even though all QN regions found in [PIN +fgmt] are present in wildtype Rnq1p. This suggests that the global fold of the prion protein and the ability of the soluble protein to access this conformation contributes to the transmission barrier. Furthermore, crossing the transmission barrier results in the creation of distinct [PIN+] strains, which are the first yeast prion strains reported to arise from transmission.;Transmission barriers are protective in that they can serve to limit infection, yet, crossing a transmission barrier can result in the creation of new strains that may have new transmissibility. Transmission barriers between species are attributed to amino acid mismatches in recognition elements between the prion protein and the soluble protein. Findings presented here suggest that the recognition element should be considered in the context of the global fold of the prion protein. |
