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PrP\n                    <jats:sup>C<\/jats:sup>\n                    \u03b2\u2010endoproteolysis to the C2 fragment allows PrP\n                    <jats:sup>S<\/jats:sup>\n                    <jats:sup>c<\/jats:sup>\n                    formation, while \u03b1\u2010endoproteolysis blocks production. To examine the OR, we used structure\u2010directed design to make novel alleles, \u2018S1\u2019 and \u2018S3\u2019, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion\u2010infected S1 and S3 transgenic mice both accumulated similar low levels of PrP\n                    <jats:sup>S<\/jats:sup>\n                    <jats:sup>c<\/jats:sup>\n                    and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2\u00a0fragment in the brain by a mechanism distinct from metal\u2010catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrP\n                    <jats:sup>S<\/jats:sup>\n                    <jats:sup>c<\/jats:sup>\n                    and infectivity can either uncouple or engage to drive the onset of clinical disease.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404588","type":"journal-article","created":{"date-parts":[[2015,2,6]],"date-time":"2015-02-06T23:08:07Z","timestamp":1423264087000},"page":"339-356","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation"],"prefix":"10.1038","volume":"7","author":[{"given":"Agnes","family":"Lau","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Daude","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles E","family":"Mays","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric D","family":"Walter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Aglietti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert CC","family":"Mercer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serene","family":"Wohlgemuth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"van der Merwe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hristina","family":"Gapeshina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Grams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beipei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Wille","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aru","family":"Balachandran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerold","family":"Schmitt\u2010Ulms","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiri G","family":"Safar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenn L","family":"Millhauser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Westaway","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,2,6]]},"reference":[{"key":"BFEMMM201404588_CR1","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nn.3120","volume":"15","author":"A Aguzzi","year":"2012","unstructured":"Aguzzi A, Falsig J (2012) Prion propagation, toxicity and degradation. 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