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Structural changes of the prion protein in lipid membranes leading to aggregation and fibrillization
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UNSPECIFIED (2003) Structural changes of the prion protein in lipid membranes leading to aggregation and fibrillization. BIOCHEMISTRY, 42 (11). pp. 3295-3304. doi:10.1021/bi026872q ISSN 0006-2960.
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Official URL: http://dx.doi.org/10.1021/bi026872q
Abstract
Prion diseases are associated with a major refolding event of the normal cellular prion protein, PrPC, where the predominantly alpha-helical and random coil structure of PrPC is converted into a beta-sheet-rich aggregated form, PrPSc. Under normal physiological conditions PrPC is attached to the outer leaflet of the plasma membrane via a GPI anchor, and it is plausible that an interaction between PrP and lipid membranes could be involved in the conversion of PrPC into PrPSc. Recombinant PrP can be refolded into an alpha-helical structure, designated alpha-PrP isoform, or into beta-sheet-rich states, designated beta-PrP isoform. The current study investigates the binding of beta-PrP to model lipid membranes and compares the structural changes in alpha- and beta-PrP induced upon membrane binding. beta-PrP binds to negatively charged POPG membranes and to raft membranes composed of DPPC, cholesterol, and sphingomyelin. Binding of beta-PrP to raft membranes results in substantial unfolding of beta-PrP. This membrane-associated largely unfolded state of PrP is slowly converted into fibrils. In contrast, beta-PrP and alpha-PrP gain structure with POPG membranes, which instead leads to amorphous aggregates. Furthermore, binding of beta-PrP to POPG has a disruptive effect on the integrity of the lipid bilayer, leading to total release of vesicle contents, whereas raft vesicles are not destabilized upon binding of beta-PrP.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry | ||||
Journal or Publication Title: | BIOCHEMISTRY | ||||
Publisher: | AMER CHEMICAL SOC | ||||
ISSN: | 0006-2960 | ||||
Official Date: | 25 March 2003 | ||||
Dates: |
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Volume: | 42 | ||||
Number: | 11 | ||||
Number of Pages: | 10 | ||||
Page Range: | pp. 3295-3304 | ||||
DOI: | 10.1021/bi026872q | ||||
Publication Status: | Published |
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