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A scrapie-like unfolding intermediate of the prion protein domain PrP(121-231) induced by acidic pH


Hornemann, S; Glockshuber, R (1998). A scrapie-like unfolding intermediate of the prion protein domain PrP(121-231) induced by acidic pH. Proceedings of the National Academy of Sciences of the United States of America, 95(11):6010-6014.

Abstract

The infectious agent of transmissible spongiform encephalopathies is believed to consist of an oligomeric isoform, PrPSc, of the monomeric cellular prion protein, PrPC. The conversion of PrPC to PrPSc is characterized by a decrease in alpha-helical structure, an increase in beta-sheet content, and the formation of PrPSc amyloid. Whereas the N-terminal part of PrPC comprising residues 23-120 is flexibly disordered, its C-terminal part, PrP(121-231), forms a globular domain with three alpha-helices and a small beta-sheet. Because the segment of residues 90-231 is protease-resistant in PrPSc, it is most likely structured in the PrPSc form. The conformational change of the segment containing residues 90-120 thus constitutes the minimal structural difference between PrPC and a PrPSc monomer. To test whether PrP(121-231) is also capable to undergo conformational transitions, we analyzed its urea-dependent unfolding transitions at neutral and acidic pH. We identified an equilibrium unfolding intermediate of PrP(121-231) that is exclusively populated at acidic pH and shows spectral characteristics of a beta-sheet protein. The intermediate is in rapid equilibrium with native PrP(121-231), significantly populated in the absence of urea at pH 4.0, and may have important implications for the presumed formation of PrPSc during endocytosis.

Abstract

The infectious agent of transmissible spongiform encephalopathies is believed to consist of an oligomeric isoform, PrPSc, of the monomeric cellular prion protein, PrPC. The conversion of PrPC to PrPSc is characterized by a decrease in alpha-helical structure, an increase in beta-sheet content, and the formation of PrPSc amyloid. Whereas the N-terminal part of PrPC comprising residues 23-120 is flexibly disordered, its C-terminal part, PrP(121-231), forms a globular domain with three alpha-helices and a small beta-sheet. Because the segment of residues 90-231 is protease-resistant in PrPSc, it is most likely structured in the PrPSc form. The conformational change of the segment containing residues 90-120 thus constitutes the minimal structural difference between PrPC and a PrPSc monomer. To test whether PrP(121-231) is also capable to undergo conformational transitions, we analyzed its urea-dependent unfolding transitions at neutral and acidic pH. We identified an equilibrium unfolding intermediate of PrP(121-231) that is exclusively populated at acidic pH and shows spectral characteristics of a beta-sheet protein. The intermediate is in rapid equilibrium with native PrP(121-231), significantly populated in the absence of urea at pH 4.0, and may have important implications for the presumed formation of PrPSc during endocytosis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Multidisciplinary
Uncontrolled Keywords:Multidisciplinary
Language:English
Date:26 May 1998
Deposited On:11 Nov 2020 10:47
Last Modified:01 Dec 2020 14:19
Publisher:National Academy of Sciences
ISSN:0027-8424
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1073/pnas.95.11.6010
PubMed ID:9600908

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