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000909761 245__ $$aMet/Val129 polymorphism of the full-length human prion protein dictates distinct pathways of amyloid formation
000909761 260__ $$aBethesda, MD.$$bAmerican Soc. for Biochemistry and Molecular Biology$$c2022
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000909761 520__ $$aMethionine/valine polymorphism at position 129 of the human prion protein, huPrP, is tightly associated with the pathogenic phenotype, disease progress, and age of onset of neurodegenerative diseases such as Creutzfeldt–Jakob disease or Fatal Familial Insomnia. This raises the question of whether and how the amino acid type at position 129 influences the structural properties of huPrP, affecting its folding, stability, and amyloid formation behavior. Here, our detailed biophysical characterization of the 129M and 129V variants of recombinant full-length huPrP(23–230) by amyloid formation kinetics, CD spectroscopy, molecular dynamics simulations, and sedimentation velocity analysis reveals differences in their aggregation propensity and oligomer content, leading to deviating pathways for the conversion into amyloid at acidic pH. We determined that the 129M variant exhibits less secondary structure content before amyloid formation and higher resistance to thermal denaturation compared to the 129V variant, whereas the amyloid conformation of both variants shows similar thermal stability. Additionally, our molecular dynamics simulations and rigidity analyses at the atomistic level identify intramolecular interactions responsible for the enhanced monomer stability of the 129M variant, involving more frequent minimum distances between E196 and R156, forming a salt bridge. Removal of the N-terminal half of the 129M full-length variant diminishes its differences compared to the 129V full-length variant and highlights the relevance of the flexible N terminus in huPrP. Taken together, our findings provide insight into structural properties of huPrP and the effects of the amino acid identity at position 129 on amyloid formation behavior.
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000909761 7001_ $$0P:(DE-Juel1)180739$$aBolakhrif, Najoua$$b1
000909761 7001_ $$00000-0002-6429-0911$$aKaiser, Jesko$$b2
000909761 7001_ $$0P:(DE-Juel1)162443$$aNagel-Steger, Luitgard$$b3
000909761 7001_ $$0P:(DE-Juel1)145165$$aGremer, Lothar$$b4
000909761 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b5
000909761 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b6$$eCorresponding author
000909761 77318 $$2Crossref$$3journal-article$$a10.1016/j.jbc.2022.102430$$bElsevier BV$$d2022-10-01$$n10$$p102430$$tJournal of Biological Chemistry$$v298$$x0021-9258$$y2022
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000909761 8564_ $$uhttps://juser.fz-juelich.de/record/909761/files/1-s2.0-S0021925822008730-main.pdf$$yOpenAccess
000909761 8564_ $$uhttps://juser.fz-juelich.de/record/909761/files/Revised_Manuscript_20220812.pdf$$yOpenAccess
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