Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues.
Soluble oligomers of Abeta42 peptide are believed to play a major role in the pathogenesis of Alzheimer disease (AD). It was recently found that at least some of the neurotoxic effects of these oligomers may be mediated by specific binding to the prion protein, PrP(C), on the cell surface (Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., and Strittmatter, S. M. (2009) Nature 457, 1128-1132). Here we characterized the interaction between synthetic Abeta42 oligomers and the recombinant human prion protein (PrP) using two biophysical techniques: site-directed spin labeling and surface plasmon resonance. Our data indicate that this binding is highly specific for a particular conformation adopted by the peptide in soluble oligomeric species. The binding appears to be essentially identical for the Met(129) and Val(129) polymorphic forms of human PrP, suggesting that the role of PrP codon 129 polymorphism as a risk factor in AD is due to factors unrelated to the interaction with Abeta oligomers. It was also found that in addition to the previously identified approximately 95-110 segment, the second region of critical importance for the interaction with Abeta42 oligomers is a cluster of basic residues at the extreme N terminus of PrP (residues 23-27). The deletion of any of these segments results in a major loss of the binding function, indicating that these two regions likely act in concert to provide a high affinity binding site for Abeta42 oligomers. This insight may help explain the interplay between the postulated protective and pathogenic roles of PrP in AD and may contribute to the development of novel therapeutic strategies as well.
Chen
Shugui
S
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Yadav
Satya P
SP
Surewicz
Witold K
WK
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011110:Polymorphism, Genetic; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D013113:Spin Labels; D020349:Surface Plasmon Resonance
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; D013113:Spin Labels