Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region
| Autor: | Nigel M. Hooper, W. Sumudhu S. Perera |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
PrPSc Proteins
Prions Protein Conformation media_common.quotation_subject animal diseases Mutant Rodentia Biology Endocytosis medicine.disease_cause General Biochemistry Genetics and Molecular Biology Prion Diseases Metal medicine Animals PrPC Proteins Internalization Histidine media_common Mutation Agricultural and Biological Sciences(all) Biochemistry Genetics and Molecular Biology(all) Neurodegeneration medicine.disease Cell biology nervous system diseases Zinc Biochemistry visual_art visual_art.visual_art_medium General Agricultural and Biological Sciences Copper Function (biology) |
| Zdroj: | Current Biology. (7):519-523 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/S0960-9822(01)00147-6 |
| Popis: | The neurodegenerative spongiform encephalopathies, or prion diseases, are characterized by the conversion of the normal cellular form of the prion protein PrP C to a pathogenic form, PrP Sc [1]. There are four copies of an octarepeat PHGG(G/S)WGQ that specifically bind Cu 2+ ions within the N-terminal half of PrP C [2–4]. This has led to proposals that prion diseases may, in part, be due to abrogation of the normal cellular role of PrP C in copper homeostasis [5]. Here, we show that murine PrP C is rapidly endocytosed upon exposure of neuronal cells to physiologically relevant concentrations of Cu 2+ or Zn 2+ , but not Mn 2+ . Deletion of the four octarepeats or mutation of the histidine residues (H68/76 dyad) in the central two repeats abolished endocytosis, indicating that the internalization of PrP C is governed by metal binding to the octarepeats. Furthermore, a mutant form of PrP that contains nine additional octarepeats and is associated with familial prion disease [6] failed to undergo Cu 2+ -mediated endocytosis. For the first time, these results provide evidence that metal ions can promote the endocytosis of a mammalian prion protein in neuronal cells and that neurodegeneration associated with some prion diseases may arise from the ablation of this function due to mutation of the octarepeat region. |
| Databáze: | OpenAIRE |
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