title: Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+].
abstract: The yeast prion [PSI(+)] provides an epigenetic mechanism for the inheritance of new phenotypes through self-perpetuating changes in protein conformation. [PSI(+)] is a nonfunctional, ordered aggregate of the translation termination factor Sup35p that influences new Sup35 proteins to adopt the same state. The N-terminal region of Sup35p plays a central role in prion induction and propagation. The C-terminal region provides translation termination activity. The function of the highly charged, conformationally flexible middle region (M) is unknown. An M deletion mutant was capable of existing in either the prion or the nonprion state, but in either case it was mostly insoluble. Substituting a charged synthetic polypeptide for M restored solubility, but the prions formed by this variant were mitotically very unstable. Substituting charged flexible regions from two other proteins for M created variants that acquired prion states (defined as self-perpetuating changes in function transferred to them from wild-type [PSI(+)] elements), but had profoundly different properties. One was soluble in both the prion and the nonprion form, mitotically stable but meiotically unstable, and cured by guanidine HCl but not by alterations in heat shock protein 104 (Hsp104p). The other could only maintain the prion state in the presence of wild-type protein, producing Mendelian segregation patterns. The unique character of these M variants, all carrying the same N-terminal prion-determining region, demonstrate the importance of M for [PSI(+)] and suggest that a much wider range of epigenetic phenomena might be based on self-perpetuating, prion-like changes in protein conformation than suggested by our current methods for defining prion states.
authors.affiliation: Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, IL 60637, USA.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Liu
authors.forename: Neal
authors.initials: N
authors.lastname: Sondheimer
authors.forename: Susan L
authors.initials: SL
authors.lastname: Lindquist
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D026942:DNA Topoisomerases / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000235:genetics; D010454:Peptide Termination Factors; D011328:Prions / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D017931:DNA Primers; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D026942:DNA Topoisomerases