The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein

• Published in: The EMBO journal 2003-07, Vol.22 (14), p.3591-3601
• Main Authors: Sunyach, Claire, Jen, Angela, Deng, Juelin, Fitzgerald, Kathleen T., Frobert, Yveline, Grassi, Jacques, McCaffrey, Mary W., Morris, Roger
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line; Cells, Cultured; coated pits; Coated Pits, Cell-Membrane - metabolism; Coated Pits, Cell-Membrane - ultrastructure; Disulfides - chemistry; EMBO20; EMBO24; Endocytosis; Glycosylphosphatidylinositols - metabolism; GPI; Kinetics; lipid rafts; Membrane Microdomains - metabolism; Mice; Molecular Sequence Data; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma - ultrastructure; Neurons, Afferent - cytology; Neurons, Afferent - metabolism; Neurons, Afferent - ultrastructure; Protein Binding; Protein Structure, Tertiary; PrPC Proteins - chemistry; PrPC Proteins - genetics; PrPC Proteins - metabolism; PrPC Proteins - ultrastructure; Receptors, Transferrin - metabolism; Receptors, Transferrin - ultrastructure; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - ultrastructure; sphingolipids; Thy-1 Antigens - metabolism; Thy-1 Antigens - ultrastructure
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdg344

The mode of internalization of glycosylphosphatidylinositol‐anchored proteins, lacking any cytoplasmic domain by which to engage adaptors to recruit them into coated pits, is problematical; that of prion protein in particular is of interest since its cellular trafficking appears to play an essential role in its pathogenic conversion. Here we demonstrate, in primary cultured neurons and the N2a neural cell line, that prion protein is rapidly and constitutively endocytosed. While still on the cell surface, prion protein leaves lipid ‘raft’ domains to enter non‐raft membrane, from which it enters coated pits. The N‐terminal domain (residues 23–107) of prion protein is sufficient to direct internalization, an activity dependent upon its initial basic residues (NH 2 ‐KKRPKP). The effect of this changing membrane environment upon the susceptibility of prion protein to pathogenic conversion is discussed.