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Originally published In Press as doi:10.1074/jbc.M007331200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 16, 13388-13394, April 20, 2001
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Prion Protein Contains a Second Endoplasmic Reticulum Targeting Signal Sequence Located at Its C Terminus*

Christina Hölscher, Ute C. Bach, and Bernhard DobbersteinDagger

From the Zentrum für Molekulare Biologie der Universität Heidelberg, Postfach 106249, 69052 Heidelberg, Germany

Prion protein (PrP) is synthesized at the membrane of the endoplasmic reticulum (ER) in three different topological forms as follows: a fully translocated one (secPrP) and two with opposite orientations in the membrane (NtmPrP and CtmPrP). We asked whether other signal sequences exist in the PrP, other than the N-terminal signal sequence, that contribute to its topological diversity. In vitro translocation assays showed that PrP lacking its N-terminal signal sequence could still translocate into ER microsomes, although at reduced efficiency. Deletion of each of the two hydrophobic regions in PrP revealed that the C-terminally located hydrophobic region (TM2) can function as second signal sequence in PrP. Translocation mediated by the TM2 alone can occur post-translationally and yields mainly CtmPrP, which is implicated in some forms of neurodegeneration in prion diseases. We conclude that, in vitro, PrP can insert into ER membranes co- and post-translationally and can use two different signal sequences. We propose that the unusually complex topology of PrP results from the differential utilization of two signal sequences in PrP.

* This work was supported by Deutsche Forschungsgemeinschaft Grant Do 199/11-1.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.

Dagger To whom correspondence should be addressed. E-mail: dobberstein@ zmbh.uni-heidelberg.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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