Mechanism of cross-species prion transmission: an infectious conformation compatible with two highly divergent yeast prion proteins.
Efficiency of interspecies prion transmission decreases as the primary structures of the infectious proteins diverge. Yet, a single prion protein can misfold into multiple infectious conformations, and such differences in "strain conformation" also alter infection specificity. Here, we explored the relationship between prion strains and species barriers by creating distinct synthetic prion forms of the yeast prion protein Sup35. We identified a strain conformation of Sup35 that allows transmission from the S. cerevisiae (Sc) Sup35 to the highly divergent C. albicans (Ca) Sup35 both in vivo and in vitro. Remarkably, cross-species transmission leads to a novel Ca strain that in turn can infect the Sc protein. Structural studies reveal strain-specific conformational differences in regions of the prion domain that are involved in intermolecular contacts. Our findings support a model whereby strain conformation is the critical determinant of cross-species prion transmission while primary structure affects transmission specificity by altering the spectrum of preferred amyloid conformations.
Tanaka
Motomasa
M
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA.
Chien
Peter
P
Yonekura
Koji
K
Weissman
Jonathan S
JS
D000682:Amyloid / Q000737:chemistry*; D002176:Candida albicans / Q000378:metabolism; D003001:Cloning, Molecular; D005656:Fungal Proteins / Q000737:chemistry*; D010454:Peptide Termination Factors; D017096:Prion Diseases / Q000635:transmission*; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*
D000682:Amyloid; D005656:Fungal Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C459790:Sup35 protein, Candida albicans