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dc.contributor.authorSpagnolli, Giovanni
dc.contributor.authorRigoli, Marta
dc.contributor.authorOrioli, Simone
dc.contributor.authorSevillano, Alejandro M.
dc.contributor.authorFaccioli, Pietro
dc.contributor.authorWille, Holger
dc.contributor.authorBiasini, Emiliano
dc.contributor.authorRodríguez Requena, Jesús
dc.date.accessioned2020-03-26T13:32:20Z
dc.date.available2020-03-26T13:32:20Z
dc.date.issued2019
dc.identifier.citationSpagnolli G, Rigoli M, Orioli S, Sevillano AM, Faccioli P, et al. (2019) Full atomistic model of prion structure and conversion. PLOS Pathogens 15(7): e1007864. https://doi.org/10.1371/journal.ppat.1007864
dc.identifier.issn1553-7366
dc.identifier.urihttp://hdl.handle.net/10347/20930
dc.description.abstractPrions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) of the cellular prion protein (PrPC), caused epidemic and epizootic episodes [1]. Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register- β-Sheet (PIRIBS) [2] or β-solenoid conformations [3]. Similar folding models have also been proposed for PrPSc, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrPSc is structured as a 4-rung β-solenoid (4RβS) [4, 5]. Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrPSc, based on the 4RβS architecture. The stability of this new PrPSc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring β-solenoid. Importantly, the 4RβS arrangement allowed the first simulation of the sequence of events underlying PrPC conversion into PrPSc. This study provides the most updated, experimentally- driven and physically-coherent model of PrPSc, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions.
dc.description.sponsorshipJRR was funded by grants BFU2017-86692-P and BFU2013-48436-C2-1-P from the Spanish Ministries of Economy and Competitiveness, and Education and Science, respectively, both partially including FEDER funds from the European Union. This work was also supported by a grant from Fondazione Telethon (Italy, TCP14009). GS is a recipient of a fellowship from Fondazione Telethon. EB is an Assistant Telethon Scientist at the Dulbecco Telethon Institute. HW acknowledges support through grant 201600029 from the Alberta Prion Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
dc.language.isoeng
dc.publisherPLOS
dc.rights© 2019 Spagnolli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleFull atomistic model of prion structure and conversion
dc.typejournal article
dc.identifier.doi10.1371/journal.ppat.1007864
dc.relation.publisherversionhttps://doi.org/10.1371/journal.ppat.1007864
dc.type.hasVersionVoR
dc.identifier.essn1553-7374
dc.rights.accessRightsopen access
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina
dc.description.peerreviewedSI


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 © 2019 Spagnolli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited





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