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Originally published In Press as doi:10.1074/jbc.M209942200 on January 29, 2003

J. Biol. Chem., Vol. 278, Issue 17, 14961-14970, April 25, 2003
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Determinants of the in Vivo Folding of the Prion Protein
A BIPARTITE FUNCTION OF HELIX 1 IN FOLDING AND AGGREGATION*

Konstanze F. Winklhofer, Johanna Heske, Ulrich Heller, Anja Reintjes, Walter MuranyiDagger , Ismail Moarefi, and Jörg Tatzelt§

From the Department of Cellular Biochemistry, Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany and Dagger  Genecenter Munich, Max-von-Pettenkofer-Institut für Virologie, Ludwig-Maximilians-Universität, D-81377 Munich, Germany

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.

* This work was supported by Deutsche Forschungsgemeinschaft Grants TA 167/2 and SFB 596 and a grant from the Bayerische Staatsminister für Wissenschaft, Forschung und Kunst (for Prion, MPI3).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 49-89-8578-2208; Fax: 49-89-8578-2211; E-mail: tatzelt@biochem.mpg.de.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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