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

Authors
  • Kaneko, K
  • Vey, M
  • Scott, M
  • Pilkuhn, S
  • Cohen, F E
  • Prusiner, S B
Type
Published Article
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publication Date
Mar 18, 1997
Volume
94
Issue
6
Pages
2333–2338
Identifiers
PMID: 9122195
Source
Medline
License
Unknown

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.

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