Genetic and epigenetic control of the efficiency and fidelity of cross-species prion transmission.
Self-perpetuating amyloid-based protein isoforms (prions) transmit neurodegenerative diseases in mammals and phenotypic traits in yeast. Although mechanisms that control species specificity of prion transmission are poorly understood, studies of closely related orthologues of yeast prion protein Sup35 demonstrate that cross-species prion transmission is modulated by both genetic (specific sequence elements) and epigenetic (prion variants, or 'strains') factors. Depending on the prion variant, the species barrier could be controlled at the level of either heterologous co-aggregation or conversion of the aggregate-associated heterologous protein into a prion polymer. Sequence divergence influences cross-species transmission of different prion variants in opposing ways. The ability of a heterologous prion domain to either faithfully reproduce or irreversibly switch the variant-specific prion patterns depends on both sequence divergence and the prion variant. Sequence variations within different modules of prion domains contribute to transmission barriers in different cross-species combinations. Individual amino acid substitutions within short amyloidogenic stretches drastically alter patterns of cross-species prion conversion, implicating these stretches as major determinants of species specificity.
Chen
Buxin
B
School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30332-0230, USA.
Bruce
Kathryn L
KL
Newnam
Gary P
GP
Gyoneva
Stefka
S
Romanyuk
Andrey V
AV
Chernoff
Yury O
YO
D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D022761:Gene Transfer, Horizontal; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment
D000682:Amyloid; D010454:Peptide Termination Factors; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins