COOH-terminal sequence of the cellular prion protein directs subcellular trafficking and controls conversion into the scrapie isoform.

Abstract

Efficient formation of scrapie isoform of prion protein (PrP(Sc)) requires targeting PrP(Sc) by glycophosphatidyl inositol (GPI) anchors to caveolae-like domains (CLDs). Redirecting the cellular isoform of prion protein (PrP(C)) to clathrin-coated pits by creating chimeric PrP molecules with four different COOH-terminal transmembrane domains prevented the formation of PrP(Sc). To determine if these COOH-terminal transmembrane segments prevented PrP(C) from refolding into PrP(Sc) 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; PrP(Sc) was formed from GPI-anchored PrP(C) but not from transmembrane PrP(C). Our findings argue that PrP(Sc) formation is restricted to a specific subcellular compartment and as such, it is likely to involve auxiliary macromolecules found within CLDs.