The fate of PrP GPI-Anchor Signal Peptide is modulated by P238S pathogenic mutation.
Résumé
: GPI Anchored proteins are localized to the plasma membrane via a C-terminally linked glycosylphosphatidylinositol (GPI) anchor. The GPI anchor is added concomitantly to the cleavage of the carboxy-terminal GPI-anchor signal sequence, thereby causing the release of a C-terminal hydrophobic peptide, whose fate has not yet been investigated. Here we followed the fate of the GPI-attachment signal of the prion protein (PrP), a protein implicated in various types of transmissible neurodegenerative spongiform encephalopathies (TSE). PrP GPI-anchor signal sequence shows a remarkable and unusual degree of conservation across the species and contains two point mutations (M232R/T and P238S) that are responsible for genetic forms of prion disorders. We show that PrP GPI-anchor signal peptide, but not the one from an unrelated GPI-anchored protein (Folate Receptor), undergoes degradation via the proteasome. Moreover, the P238S point mutation partially protects PrP GPI-anchor signal peptide from degradation. Our data provide the first attempt to address the fate of a GPI-anchor signal peptide and identify a role for the P238S mutation, suggesting the possibility that PrP GPI-anchor signal peptide could play a role in neurodegenerative prion diseases.