title: Prion protein/protein interactions: fusion with yeast Sup35p-NM modulates cytosolic PrP aggregation in mammalian cells.
abstract: In mammalian prion diseases, an abnormally folded, aggregated form of the prion protein (PrP(Sc)) appears to catalyze a conformational switch of its cellular isoform (PrP(C)) to an aggregated state. A similar prion-like phenomenon has been reported for the Saccharomyces cerevisiae translation termination factor Sup35p that can adopt a self-propagating conformation. We have compared aggregation propensities of chimeric proteins derived from the Sup35p prion domain NM and PrP in vitro and in the cytosol of mammalian cells. Sup35p-NM and PrP displayed strikingly different aggregation behaviors when expressed in mammalian cells, with NM remaining soluble and cytosolic PrP spontaneously aggregating due to the globular domain of PrP. When fused to PrP(90-230), Sup35p-M exhibited an inhibitory effect for nucleation but increased aggregate growth, potentially by facilitating recruitment of newly synthesized chimeric proteins into the growing aggregates. This effect, however, could, to some extent, be counteracted by the prion-forming region Sup35p-N, thereby increasing aggregate frequency. Interestingly, a lowered nucleation rate was also observed in the presence of the amino-terminal region of PrP, suggesting that Sup35p-M and PrP(23-90) share some biological function in prion protein assembly. Our results provide new insights into prion protein aggregation behaviors, demonstrating the impact of dynamic interactions between prion domains and suggesting that aggregation of yeast and mammalian prion proteins is strongly influenced by yet unidentified cellular conditions or factors.
authors.affiliation: Institute of Virology, Technical University of Munich, Trogerstr. 30, 81675 Munich, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Krammer
authors.forename: Michael H
authors.initials: MH
authors.lastname: Suhre
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Claudia
authors.initials: C
authors.lastname: Diemer
authors.forename: Simone
authors.initials: S
authors.lastname: Hess
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Schätzl
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheibel
authors.forename: Ina
authors.initials: I
authors.lastname: Vorberg
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010454:Peptide Termination Factors; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D010454:Peptide Termination Factors; D011328:Prions; D011993:Recombinant Fusion Proteins; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins