A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers

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dc.contributor.authorNoble, Geoffrey P.en
dc.contributor.authorWang, Daphne W.en
dc.contributor.authorWalsh, Daniel J.en
dc.contributor.authorBarone, Justin R.en
dc.contributor.authorMiller, Michael B.en
dc.contributor.authorNishina, Koren A.en
dc.contributor.authorLi, Shengen
dc.contributor.authorSupattapone, Surachaien
dc.contributor.departmentBiological Systems Engineeringen
dc.date.accessioned2018-12-04T18:42:14Zen
dc.date.available2018-12-04T18:42:14Zen
dc.date.issued2015-06-30en
dc.description.abstractInfectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >10(5)-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure.en
dc.description.sponsorshipThis work was funded by a research grant from the National Institutes of Health (2R01 NS046478) to SS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.format.extent21 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1005017en
dc.identifier.eissn1553-7374en
dc.identifier.issn1553-7366en
dc.identifier.issue6en
dc.identifier.othere1005017en
dc.identifier.pmid26125623en
dc.identifier.urihttp://hdl.handle.net/10919/86220en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectscrapie prion proteinen
dc.subjecttransmissible spongiform encephalopathyen
dc.subjectin-vitroen
dc.subjecthydrogen/deuterium exchangeen
dc.subjectmammalian prionsen
dc.subjecthydrogen-exchangeen
dc.subjectmass-spectrometryen
dc.subjectstrain propertiesen
dc.subjectamyloid fibrilsen
dc.subjecttransgenic miceen
dc.titleA Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformersen
dc.title.serialPLOS Pathogensen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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