The C-terminal Globular Domain of the Prion Protein Is Necessary and Sufficient for Import into the Endoplasmic Reticulum

Johanna Heske, Ulrich Heller, Konstanze F. Winklhofer, Jörg Tatzelt
2003 Journal of Biological Chemistry  
The mammalian prion protein (PrP) is composed of an unstructured flexible N-terminal region and a C-terminal globular domain. We examined the import of PrP into the endoplasmic reticulum (ER) of neuronal cells and show that information present in the C-terminal globular domain is required for ER import of the N terminus. N-terminal fragments of PrP, devoid of structural domains located in the C terminus, remained in the cytosol with an uncleaved signal peptide and were rapidly degraded by the
more » ... y degraded by the proteasome. Conversely, the separate C-terminal domain of PrP, comprising the highly ordered helix 2-loop-helix 3 motif, was entirely imported into the ER. As a consequence, two PrP mutants linked to inherited prion disease in humans, PrP-W145Stop and PrP-Q160Stop, were partially retained in the cytosol. The cytosolic fraction was characterized by an uncleaved N-terminal signal peptide and was degraded by the proteasome. Our study identified a new regulatory element in the C-terminal globular domain of PrP necessary and sufficient to promote import of PrP into the ER.
doi:10.1074/jbc.m309570200 pmid:14645231 fatcat:tr4yd26r7vh2bay7wrfj2vg6sy