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Cryo-EM of prion strains from the same genotype of host identifies conformational determinants

Prion strains in a given type of mammalian host are distinguished by differences in clinical presentation, neuropathological lesions, survival time, and characteristics of the infecting prion protein (PrP) assemblies. Near-atomic structures of prions from two host species with different PrP sequence...

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Autores principales: Hoyt, Forrest, Alam, Parvez, Artikis, Efrosini, Schwartz, Cindi L., Hughson, Andrew G., Race, Brent, Baune, Chase, Raymond, Gregory J., Baron, Gerald S., Kraus, Allison, Caughey, Byron
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671466/
https://www.ncbi.nlm.nih.gov/pubmed/36342968
http://dx.doi.org/10.1371/journal.ppat.1010947
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author Hoyt, Forrest
Alam, Parvez
Artikis, Efrosini
Schwartz, Cindi L.
Hughson, Andrew G.
Race, Brent
Baune, Chase
Raymond, Gregory J.
Baron, Gerald S.
Kraus, Allison
Caughey, Byron
author_facet Hoyt, Forrest
Alam, Parvez
Artikis, Efrosini
Schwartz, Cindi L.
Hughson, Andrew G.
Race, Brent
Baune, Chase
Raymond, Gregory J.
Baron, Gerald S.
Kraus, Allison
Caughey, Byron
author_sort Hoyt, Forrest
collection PubMed
description Prion strains in a given type of mammalian host are distinguished by differences in clinical presentation, neuropathological lesions, survival time, and characteristics of the infecting prion protein (PrP) assemblies. Near-atomic structures of prions from two host species with different PrP sequences have been determined but comparisons of distinct prion strains of the same amino acid sequence are needed to identify purely conformational determinants of prion strain characteristics. Here we report a 3.2 Å resolution cryogenic electron microscopy-based structure of the 22L prion strain purified from the brains of mice engineered to express only PrP lacking glycophosphatidylinositol anchors [anchorless (a) 22L]. Comparison of this near-atomic structure to our recently determined structure of the aRML strain propagated in the same inbred mouse reveals that these two mouse prion strains have distinct conformational templates for growth via incorporation of PrP molecules of the same sequence. Both a22L and aRML are assembled as stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops, with single monomers spanning the ordered fibril core. Each monomer shares an N-terminal steric zipper, three major arches, and an overall V-shape, but the details of these and other conformational features differ markedly. Thus, variations in shared conformational motifs within a parallel in-register β-stack fibril architecture provide a structural basis for prion strain differentiation within a single host genotype.
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spelling pubmed-96714662022-11-18 Cryo-EM of prion strains from the same genotype of host identifies conformational determinants Hoyt, Forrest Alam, Parvez Artikis, Efrosini Schwartz, Cindi L. Hughson, Andrew G. Race, Brent Baune, Chase Raymond, Gregory J. Baron, Gerald S. Kraus, Allison Caughey, Byron PLoS Pathog Research Article Prion strains in a given type of mammalian host are distinguished by differences in clinical presentation, neuropathological lesions, survival time, and characteristics of the infecting prion protein (PrP) assemblies. Near-atomic structures of prions from two host species with different PrP sequences have been determined but comparisons of distinct prion strains of the same amino acid sequence are needed to identify purely conformational determinants of prion strain characteristics. Here we report a 3.2 Å resolution cryogenic electron microscopy-based structure of the 22L prion strain purified from the brains of mice engineered to express only PrP lacking glycophosphatidylinositol anchors [anchorless (a) 22L]. Comparison of this near-atomic structure to our recently determined structure of the aRML strain propagated in the same inbred mouse reveals that these two mouse prion strains have distinct conformational templates for growth via incorporation of PrP molecules of the same sequence. Both a22L and aRML are assembled as stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops, with single monomers spanning the ordered fibril core. Each monomer shares an N-terminal steric zipper, three major arches, and an overall V-shape, but the details of these and other conformational features differ markedly. Thus, variations in shared conformational motifs within a parallel in-register β-stack fibril architecture provide a structural basis for prion strain differentiation within a single host genotype. Public Library of Science 2022-11-07 /pmc/articles/PMC9671466/ /pubmed/36342968 http://dx.doi.org/10.1371/journal.ppat.1010947 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Hoyt, Forrest
Alam, Parvez
Artikis, Efrosini
Schwartz, Cindi L.
Hughson, Andrew G.
Race, Brent
Baune, Chase
Raymond, Gregory J.
Baron, Gerald S.
Kraus, Allison
Caughey, Byron
Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title_full Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title_fullStr Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title_full_unstemmed Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title_short Cryo-EM of prion strains from the same genotype of host identifies conformational determinants
title_sort cryo-em of prion strains from the same genotype of host identifies conformational determinants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671466/
https://www.ncbi.nlm.nih.gov/pubmed/36342968
http://dx.doi.org/10.1371/journal.ppat.1010947
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