Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region.
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.
Perera
W S
WS
School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
Hooper
N M
NM
D000818:Animals; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D009154:Mutation; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000209:etiology* / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000378:metabolism / Q000472:pathogenicity; D011487:Protein Conformation; D012377:Rodentia / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D003300:Copper; D015032:Zinc