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dc.contributor.authorTyedmers, Jens
dc.contributor.authorTreusch, Sebastian
dc.contributor.authorDong, Jijun
dc.contributor.authorMcCaffery, J. Michael
dc.contributor.authorBevis, Brooke J.
dc.contributor.authorLindquist, Susan
dc.date.accessioned2011-03-04T19:00:56Z
dc.date.available2011-03-04T19:00:56Z
dc.date.issued2010-05
dc.date.submitted2009-12
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/61415
dc.description.abstractWhen the translation termination factor Sup35 adopts the prion state, [PSI+], the read-through of stop codons increases, uncovering hidden genetic variation and giving rise to new, often beneficial, phenotypes. Evidence suggests that prion induction involves a process of maturation, but this has never been studied in detail. To do so, we used a visually tractable prion model consisting of the Sup35 prion domain fused to GFP (PrD-GFP) and overexpressed it to achieve induction in many cells simultaneously. PrD-GFP first assembled into Rings as previously described. Rings propagated for many generations before the protein transitioned into a Dot structure. Dots transmitted the [PSI+] phenotype through mating and meiosis, but Rings did not. Surprisingly, the underlying amyloid conformation of PrD-GFP was identical in Rings and Dots. However, by electron microscopy, Rings consisted of very long uninterrupted bundles of fibers, whereas Dot fibers were highly fragmented. Both forms were deposited at the IPOD, a biologically ancient compartment for the deposition of irreversibly aggregated proteins that we propose is the site of de novo prion induction. We find that oxidatively damaged proteins are also localized there, helping to explain how proteotoxic stresses increase the rate of prion induction. Curing PrD-GFP prions, by inhibiting Hsp104’s fragmentation activity, reversed the induction process: Dot cells produced Rings before PrD-GFP reverted to the soluble state. Thus, formation of the genetically transmissible prion state is a two-step process that involves an ancient system for the asymmetric inheritance of damaged proteins and heritable changes in the extent of prion fragmentation.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (GM025874)en_US
dc.description.sponsorshipEuropean Molecular Biology Organizationen_US
dc.description.sponsorshipHuman Frontier Science Program (Strasbourg, France)en_US
dc.description.sponsorshipAmerican Heart Associationen_US
dc.language.isoen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1003895107en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titlePrion induction involves an ancient system for the sequestration of aggregated proteins and heritable changes in prion fragmentationen_US
dc.typeArticleen_US
dc.identifier.citationTyedmers, Jens et al. “Prion induction involves an ancient system for the sequestration of aggregated proteins and heritable changes in prion fragmentation.” Proceedings of the National Academy of Sciences 107.19 (2010): 8633 -8638. ©2010 by the National Academy of Sciences.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentWhitehead Institute for Biomedical Researchen_US
dc.contributor.approverLindquist, Susan
dc.contributor.mitauthorLindquist, Susan
dc.contributor.mitauthorDong, Jijun
dc.contributor.mitauthorTreusch, Sebastian
dc.contributor.mitauthorTyedmers, Jens
dc.contributor.mitauthorBevis, Brooke J.
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsTyedmers, J.; Treusch, S.; Dong, J.; McCaffery, J. M.; Bevis, B.; Lindquist, S.en
dc.identifier.orcidhttps://orcid.org/0000-0003-1307-882X
dspace.mitauthor.errortrue
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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