title: The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc).
abstract: Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP(Sc)) binds to the cellular form (PrP(C)), generating additional molecules of PrP(Sc). While several regions of the PrP(C) molecule have been suggested to play a role in PrP(Sc) formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23-31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrP(Sc). These results, in combination with biochemical data, demonstrate that residues 23-31 represent a critical site on PrP(C) that binds to PrP(Sc) and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrP(C).
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors: Jessie A
authors: JA
authors: Turnbaugh
authors: Ursula
authors: U
authors: Unterberger
authors: Paula
authors: P
authors: Saá
authors: Tania
authors: T
authors: Massignan
authors: Brian R
authors: BR
authors: Fluharty
authors: Frederick P
authors: FP
authors: Bowman
authors: Michael B
authors: MB
authors: Miller
authors: Surachai
authors: S
authors: Supattapone
authors: Emiliano
authors: E
authors: Biasini
authors: David A
authors: DA
authors: Harris
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D006224:Cricetinae; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007114:Immunization / Q000379:methods; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D012608:Scrapie / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D010446:Peptide Fragments; D018621:PrPC Proteins; D018620:PrPSc Proteins