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Traffic. 2014 Jan;15(1):78-93. doi: 10.1111/tra.12126. Epub 2013 Oct 31.

The fate of PrP GPI-anchor signal peptide is modulated by P238S pathogenic mutation.

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1
Institut Pasteur, Unité de Trafic Membranaire et Pathogenèse, 25-28 rue du Docteur Roux, 75015, Paris, France.

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins are localized to the plasma membrane via a C-terminally linked 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). The 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 the PrP GPI-anchor signal peptide (SP), but not the one from an unrelated GPI-anchored protein (folate receptor), undergoes degradation via the proteasome. Moreover, the P238S point mutation partially protects the PrP GPI-anchor SP from degradation. Our data provide the first attempt to address the fate of a GPI-anchor SP and identify a role for the P238S mutation, suggesting the possibility that the PrP GPI-anchor SP could play a role in neurodegenerative prion diseases.

KEYWORDS:

GPI-anchor; PrP mutation; degradation; prion; proteasome; signal peptide

PMID:
24112521
DOI:
10.1111/tra.12126
[Indexed for MEDLINE]
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