NR APHW
AU Heske,J.; Heller,U.; Winklhofer,K.F.; Tatzelt,J.
TI The C-terminal globular domain of the prion protein is necessary and sufficient for import into the endoplasmic reticulum
QU The Journal of Biological Chemistry 2004 Feb 13; 279(7): 5435-43
IA http://www.jbc.org/cgi/reprint/M309570200v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=heller+u&searchid=1070286428832_4690&stored_search=&FIRSTINDEX=0&sortspec=relevance&resourcetype=1
PT journal article
AB 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 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.
MH Amino Acid Motifs; Animals; Blotting, Western; Cell Membrane/metabolism; Cell Survival; Cells, Cultured; Codon, Terminator; Cytosol/metabolism; Endopeptidase K/chemistry/pharmacology; Endoplasmic Reticulum/*metabolism; Mice; Microsomes/metabolism; Mutation; Precipitin Tests; Prions/*chemistry/metabolism; Protein Sorting Signals; Protein Structure, Tertiary; Protein Transport; Subcellular Fractions; Support, Non-U.S. Gov't; Time Factors; Transfection; Translation, Genetic
AD Department of Cellular Biochemistry, Max-Planck-Institut für Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany.
SP englisch
PO USA