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Post-translational modifications in PrP expand the conformational diversity of prions in vivo
University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA.
Case Western Reserve University, OH 44116 USA.
University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; US FDA, MD USA.
CIC bioGUNE, Spain.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 43295Article in journal (Refereed) Published
Abstract [en]

Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, 43295
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:liu:diva-136600DOI: 10.1038/srep43295ISI: 000395749700001PubMedID: 28272426OAI: diva2:1089968

Funding Agencies|National Institutes of Health [NS069566, NS076896, AI106705, NS083687]; Swedish Foundation for Strategic Research (KPRN)

Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2017-05-08

Open Access in DiVA

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