title: Site-specific structural analysis of a yeast prion strain with species-specific seeding activity.
abstract: Prion proteins misfold and aggregate into multiple infectious strain variants that possess unique abilities to overcome prion species barriers, yet the structural basis for the species-specific infectivities of prion strains is poorly understood. Therefore, we have investigated the site-specific structural properties of a promiscuous chimeric form of the yeast prion Sup35 from Saccharomyces cerevisiae and Candida albicans. The Sup35 chimera forms two strain variants, each of which selectively infect one species but not the other. Importantly, the N-terminal and middle domains of the Sup35 chimera (collectively referred to as Sup35NM) contain two prion recognition elements (one from each species) that regulate the nucleation of each strain. Mutations in either prion recognition element significantly bias nucleation of one strain conformation relative to the other. Herein, we have investigated the folding of each prion recognition element for the serine-to-arginine mutant at residue 17 of Sup35NM chimera known to promote nucleation of C. albicans strain conformation. Using cysteine-specific labeling analysis, we find that residues in the C. albicans prion recognition element are solvent-shielded, while those outside the recognition sequence (including most of those in the S. cerevisiae recognition element) are solvent-exposed. Moreover, we find that proline mutations in the C. albicans recognition sequence disrupt the prion templating activity of this strain conformation. Our structural findings reveal that differential folding of complementary and non-complementary prion recognition elements within the prion amyloid core of the Sup35NM chimera is the structural basis for its species-specific templating activity.
authors: Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.
authors: Anna Marie
authors: AM
authors: Marcelino-Cruz
authors: Moumita
authors: M
authors: Bhattacharya
authors: Aaron C
authors: AC
authors: Anselmo
authors: Peter M
authors: PM
authors: Tessier
mesh_terms: D000595:Amino Acid Sequence; D002176:Candida albicans / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010454:Peptide Termination Factors / Q000737:chemistry; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D013045:Species Specificity
chemical_list: D005656:Fungal Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C459790:Sup35 protein, Candida albicans