title: Dissociation of recombinant prion autocatalysis from infectivity.
abstract: Within the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication--that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain. (1) We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non-infectious conformer from templating the conversion of native PrP(C) substrates containing a glycosylphosphatidylinositol (GPI) anchor. (1) In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrP(C), and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication.
authors.affiliation: a Departments of Biochemistry and Medicine ; Geisel School of Medicine at Dartmouth College ; Hanover , NH USA.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Noble
authors.affiliation: a Departments of Biochemistry and Medicine ; Geisel School of Medicine at Dartmouth College ; Hanover , NH USA.
authors.forename: Surachai
authors.initials: S
authors.lastname: Supattapone
mesh_terms: D000818:Animals; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D011994:Recombinant Proteins
keywords: amyloid; cofactors; mammalian prions; recombinant prions; scrapie prion protein