COOH-TERMINAL SEQUENCE OF THE CELLULAR PRION PROTEIN DIRECTS SUBCELLULAR TRAFFICKING AND CONTROLS CONVERSION INTO THE SCRAPIE ISOFORM

Efficient formation of scrapie isoform of prion protein (PrPSc) requir es targeting PrPSc by glycophosphatidyl inositol (GPI) anchors to cave olae-like domains (CLDs). Redirecting the cellular isoform of prion pr otein (PrPC) to clathrin-coated pits by creating chimeric PrP molecule s with four different COOH-terminal transmembrane domains prevented th e formation of PrPSc, To determine if these COOH-terminal transmembran e segments prevented PrPC from refolding into PrPSc by altering the st ructure of the polypeptide, we fused the 28-aa COOH termini from the Q a protein. Two COOH-terminal Qa segments differing by a single residue direct the transmembrane protein to clathrin-coated pits or the GPI f orm to CLDs; PrPSc was formed from GPI-anchored PrPC but not from tran smembrane PrPC. Our findings argue that PrPSc formation is restricted to a specific subcellular compartment and as such, it is likely to inv olve auxiliary macromolecules found within CLDs.