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. 2020 Feb 5;165(3):535–556. doi: 10.1007/s00705-020-04529-2

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© The Author(s) 2020

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Two basic regions in the N-terminal segment of PrP and its immediate evolutionary precursors: TSE strain-specific structural differences. (A) The two polybasic regions in the intrinsically disordered N-terminus of human PrP, schematically depicted in complex with a nucleic acid (DNA for illustration), are shown fused to the globular/α-helical region of the protein established by NMR (PDB 1QM2 [236]). (B) Conservation of two basic regions in PrP and its evolutionary precursor (Shadoo/SPRN). PrP sequences (P) are Hu, human; Mo, mouse; Bo, bovine; Md, opossum (marsupial, Monodelphis domestica); Cs, mousebird (Colius striatus); Gg, chicken (Gallus gallus); Pm, viper (Protobothrops mucrosquamatus); Xl, African clawed frog (Xenopus laevis). The final three entries are prion protein 1 from zebrafish (DrP, Danio rerio), Shadoo/SPRN from zebrafish (DrS), and Shadoo/SPRN from whale shark (RtS, Rhincodon typus) which lack the C-terminal globular region and have alternative region 2 polybasic sequences (His-rich in DrP, and Arg-rich in DrS and RtS). Color code: red, highly basic (Lys/Arg); violet, basic (Asn/Gln/His); green, acidic (Asp/Glu); yellow, hydrophobic (Leu/Ile/Val/Met/Phe/Tyr). (C) TSE strains and the N-terminal region of PrP. Summary of strain-dependent cleavage sites, strain-specific antibody binding, occlusion of antibody binding, and RNA-dependent refolding of PrP. The figure shows the alignment of the N-termini of human (Hu), mouse (Mo), hamster (Ha), and bovine (Bo) PrP^C sequences (the C-terminus is depicted schematically). Regions 1 and 2 are as in panels A and B. The exact details depend on the host species (and host genotype) as well as on the strain of the agent. Strain-specific cleavages (v) are sites where high-resolution mapping (e.g., mass spectrometry) demonstrates that the precise sites of PrP proteolytic processing differ significantly between infections with different strain types [119, 128, 129, 237]. Grey and brown horizontal bars show regions that are occluded (‘cryptic’) in PrP^Sc versus PrP^C (grey) and that can also differ according to the strain of TSE [130–133], or that are occluded in exosomes from scrapie-infected cells (brown) [220]. Blue horizontal bars indicate epitopes for strain-specific antibody binding [238–240]. The epitope marked with an asterisk (*) is recognized by antibody 3F4 [241]; RNA binding to PrP in vitro occludes 3F4 binding (J-L.D, unpublished). Molecular dynamics simulations indicate that RNA bound to site 1 can lead to refolding of the polypeptide and dissolution of the first α-helical region; predicted new contacts after refolding are indicated by red bars; there may be further contacts within PrP [115]. ‘Basic’ amino acids indicated in the figure include not only K and R but also H, Q, and N, which contain positively charged groups with potential to interact with nucleic acid phosphates. The panel aims to highlight strain-specific differences and is not intended as a comprehensive survey

Fig. 1 — Two basic regions in the N-terminal segment of PrP and its immediate evolutionary precursors: TSE strain-specific structural differences. (A) The two polybasic regions in the intrinsically disordered N-terminus of human PrP, schematically depicted in complex with a nucleic acid (DNA for illustration), are shown fused to the globular/α-helical region of the protein established by NMR (PDB 1QM2 [236]). (B) Conservation of two basic regions in PrP and its evolutionary precursor (Shadoo/SPRN). PrP sequences (P) are Hu, human; Mo, mouse; Bo, bovine; Md, opossum (marsupial, Monodelphis domestica); Cs, mousebird (Colius striatus); Gg, chicken (Gallus gallus); Pm, viper (Protobothrops mucrosquamatus); Xl, African clawed frog (Xenopus laevis). The final three entries are prion protein 1 from zebrafish (DrP, Danio rerio), Shadoo/SPRN from zebrafish (DrS), and Shadoo/SPRN from whale shark (RtS, Rhincodon typus) which lack the C-terminal globular region and have alternative region 2 polybasic sequences (His-rich in DrP, and Arg-rich in DrS and RtS). Color code: red, highly basic (Lys/Arg); violet, basic (Asn/Gln/His); green, acidic (Asp/Glu); yellow, hydrophobic (Leu/Ile/Val/Met/Phe/Tyr). (C) TSE strains and the N-terminal region of PrP. Summary of strain-dependent cleavage sites, strain-specific antibody binding, occlusion of antibody binding, and RNA-dependent refolding of PrP. The figure shows the alignment of the N-termini of human (Hu), mouse (Mo), hamster (Ha), and bovine (Bo) PrP^C sequences (the C-terminus is depicted schematically). Regions 1 and 2 are as in panels A and B. The exact details depend on the host species (and host genotype) as well as on the strain of the agent. Strain-specific cleavages (v) are sites where high-resolution mapping (e.g., mass spectrometry) demonstrates that the precise sites of PrP proteolytic processing differ significantly between infections with different strain types [119, 128, 129, 237]. Grey and brown horizontal bars show regions that are occluded (‘cryptic’) in PrP^Sc versus PrP^C (grey) and that can also differ according to the strain of TSE [130–133], or that are occluded in exosomes from scrapie-infected cells (brown) [220]. Blue horizontal bars indicate epitopes for strain-specific antibody binding [238–240]. The epitope marked with an asterisk (*) is recognized by antibody 3F4 [241]; RNA binding to PrP in vitro occludes 3F4 binding (J-L.D, unpublished). Molecular dynamics simulations indicate that RNA bound to site 1 can lead to refolding of the polypeptide and dissolution of the first α-helical region; predicted new contacts after refolding are indicated by red bars; there may be further contacts within PrP [115]. ‘Basic’ amino acids indicated in the figure include not only K and R but also H, Q, and N, which contain positively charged groups with potential to interact with nucleic acid phosphates. The panel aims to highlight strain-specific differences and is not intended as a comprehensive survey