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Post-translational ...
Post-translational modifications in PrP expand the conformational diversity of prions in vivo
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- Aguilar-Calvo, Patricia (författare)
- University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA
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- Xiao, Xiangzhu (författare)
- Case Western Reserve University, OH 44116 USA
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- Bett, Cyrus (författare)
- University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; US FDA, MD USA
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- Erana, Hasier (författare)
- CIC bioGUNE, Spain
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- Soldau, Katrin (författare)
- University of Calif San Diego, CA 92093 USA
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- Castilla, Joaquin (författare)
- University of Calif San Diego, CA 92093 USA; CIC bioGUNE, Spain; Ikerbasque, Spain
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- Nilsson, Peter (författare)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Surewicz, Witold K. (författare)
- Case Western Reserve University, OH 44116 USA
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- Sigurdson, Christina J. (författare)
- University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; University of Calif Davis, CA 95616 USA
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(creator_code:org_t)
- 2017-03-08
- 2017
- Engelska.
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
- Relaterad länk:
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https://liu.diva-por... (primary) (Raw object)
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
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- ref (ämneskategori)
- art (ämneskategori)
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