NR AJIT
AU Perera,W.S.S.; Hooper,N.M.
TI Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region
QU Current Biology 2001 Apr 3; 11(7): 519-23
PT journal article
AB The neurodegenerative spongiform encephalopathies, or prion diseases, are characterized by the conversion of the normal cellular form of the prion protein PrPc to a pathogenic form, PrPsc [1]. There are four copies of an octarepeat PHGG(G/S)WGQ that specifically bind Cu(2+) ions within the N-terminal half of PrPc [2-4]. This has led to proposals that prion diseases may, in part, be due to abrogation of the normal cellular role of PrPc in copper homeostasis [5]. Here, we show that murine PrPc 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 PrPc 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.
MH Animal; Copper/metabolism/*pharmacology; *Endocytosis/drug effects; Mutation; PrPc Proteins/chemistry/genetics/*metabolism; PrPsc Proteins/metabolism; Prion Diseases/*etiology/metabolism; Prions/chemistry/metabolism/pathogenicity; Protein Conformation; Rodentia/metabolism; Support, Non-U.S. Gov't; Zinc/metabolism/*pharmacology
AD School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
SP englisch
PO England