NR AFMH
AU Hölscher,C.; Bach,U.C.; Dobberstein,B.
TI Prion protein contains a second endoplasmic reticulum targeting signal sequence located at its C terminus
QU The Journal of Biological Chemistry 2001 Apr 20; 276(16): 13388-94
PT journal article
AB Prion protein (PrP) is synthesized at the membrane of the endoplasmic reticulum (ER) in three different topological forms as follows: a fully translocated one ((sec)PrP) and two with opposite orientations in the membrane ((Ntm)PrP and (Ctm)PrP). 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 (Ctm)PrP, 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.
MH Animal; Endopeptidases/metabolism; Endoplasmic Reticulum/*metabolism; Human; Intracellular Membranes/*metabolism; Prion Diseases; Prions/*chemistry/genetics/*metabolism; Protein Processing, Post-Translational; Protein Sorting Signals; RNA, Messenger/genetics; Recombinant Proteins/chemistry/metabolism; Sequence Deletion; Support, Non-U.S. Gov't; Transcription, Genetic; Translation, Genetic
AD Zentrum für Molekulare Biologie der Universität Heidelberg, Postfach 106249, 69052 Heidelberg, Germany.
SP englisch
PO USA