Open AccessCOOH-terminal sequence of the cellular prion protein directs subcellular trafficking and controls conversion into the scrapie isoform
Author(s) -
Kiyotoshi Kaneko,
Martin Vey,
Michael Scott,
Susanne Pilkuhn,
Fred E. Cohen,
Stanley B. Prusiner
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.6.2333
Subject(s) - transmembrane protein , gene isoform , scrapie , subcellular localization , prion protein , transmembrane domain , microbiology and biotechnology , clathrin , chemistry , cellular compartment , biochemistry , membrane protein , cytoplasm , biology , membrane , endocytosis , receptor , gene , medicine , disease , pathology , cell
Efficient formation of scrapie isoform of prion protein (PrPSc ) requires targeting PrPSc by glycophosphatidyl inositol (GPI) anchors to caveolae-like domains (CLDs). Redirecting the cellular isoform of prion protein (PrPC ) to clathrin-coated pits by creating chimeric PrP molecules with four different COOH-terminal transmembrane domains prevented the formation of PrPSc . To determine if these COOH-terminal transmembrane segments prevented PrPC from refolding into PrPSc by altering the structure of the polypeptide, we fused the 28-aa COOH termini from the Qa protein. Two COOH-terminal Qa segments differing by a single residue direct the transmembrane protein to clathrin-coated pits or the GPI form to CLDs; PrPSc was formed from GPI-anchored PrPC but not from transmembrane PrPC . Our findings argue that PrPSc formation is restricted to a specific subcellular compartment and as such, it is likely to involve auxiliary macromolecules found within CLDs.