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  Determinants of the in vivo folding of the prion protein - A bipartite function of helix 1 in folding and aggregation

Winklhofer, K. F., Heske, J., Heller, U., Reintjes, A., Muranyi, W., Moarefi, I., et al. (2003). Determinants of the in vivo folding of the prion protein - A bipartite function of helix 1 in folding and aggregation. Journal of Biological Chemistry, 278(17), 14961-14970.

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Genre: Journal Article
Alternative Title : J. Biol. Chem.

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 Creators:
Winklhofer, K. F.1, Author              
Heske, J.1, Author              
Heller, U.1, Author              
Reintjes, A.1, Author              
Muranyi, W., Author
Moarefi, I.1, Author              
Tatzelt, J.1, Author              
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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 Abstract: Misfolding of the mammalian prion protein (PrP) is implicated in the pathogenesis of prion diseases. We analyzed wild type PrP in comparison with different PrP mutants and identified determinants of the in vivo folding pathway of PrP. The complete N terminus of PrP including the putative transmembrane domain and the first beta-strand could be deleted without interfering with PrP maturation. Helix 1, however, turned out to be a major determinant of PrP folding. Disruption of helix 1 prevented attachment of the glycosylphosphatidylinositol (GPI) anchor and the formation of complex N-linked glycans; instead, a high mannose PrP glycoform was secreted into the cell culture supernatant. In the absence of a C-terminal membrane anchor, however, helix 1 induced the formation of unglycosylated and partially protease-resistant PrP aggregates. Moreover, we could show that the C-terminal GPI anchor signal sequence, independent of its role in GPI anchor attachment, mediates core glycosylation of nascent PrP. Interestingly, conversion of high mannose glycans to complex type glycans only occurred when PrP was membrane-anchored. Our study indicates a bipartite function of helix 1 in the maturation and aggregation of PrP and emphasizes a critical role of a membrane anchor in the formation of complex glycosylated PrP.

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Language(s): eng - English
 Dates: 2003-04-25
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 41391
ISI: 000182516100051
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Title: Journal of Biological Chemistry
  Alternative Title : J. Biol. Chem.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 278 (17) Sequence Number: - Start / End Page: 14961 - 14970 Identifier: ISSN: 0021-9258