title: Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol.
abstract: A rare conformation of the prion protein, PrPSc, is found only in mammals with transmissible prion diseases and represents either the infectious agent itself or a major component of it. The mechanism for initiating PrPSc formation is unknown. We report that PrP retrogradely transported out of the endoplasmic reticulum produced both amorphous aggregates and a PrPSc-like conformation in the cytosol. The distribution between these forms correlated with the rate of appearance in the cytosol. Once conversion to the PrPSc-like conformation occurred, it was sustained. Thus, PrP has an inherent capacity to promote its own conformational conversion in mammalian cells. These observations might explain the origin of PrPSc.
authors.affiliation: Howard Hughes Medical Institute (HHMI), University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Ma
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D019286:Endopeptidase K / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons; D009842:Oligopeptides / Q000494:pharmacology; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D018620:PrPSc Proteins; D011328:Prions; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C067713:lactacystin; D019286:Endopeptidase K; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine; C078846:epoxomicin