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Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126

journal contribution
posted on 2001-07-10, 00:00 authored by M F Jobling, X Huang, L R Stewart, K J Barnham, C Curtain, I Volitakis, M Perugini, A R White, R A Cherny, C L Masters, Colin BarrowColin Barrow, S J Collins, A I Bush, R Cappai
The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible spongiform encephalopathies. A peptide encompassing residues 106-126 of human PrP (PrP106-126) is neurotoxic in vitro due its adoption of an amyloidogenic fibril structure. The Alzheimer's disease amyloid beta peptide (Abeta) also undergoes fibrillogenesis to become neurotoxic. Abeta aggregation and toxicity is highly sensitive to copper, zinc, or iron ions. We show that PrP106-126 aggregation, as assessed by turbidometry, is abolished in Chelex-100-treated buffer. ICP-MS analysis showed that the Chelex-100 treatment had reduced Cu(2+) and Zn(2+) levels approximately 3-fold. Restoring Cu(2+) and Zn(2+) to their original levels restored aggregation. Circular dichroism showed that the Chelex-100 treatment reduced the aggregated beta-sheet content of the peptide. Electron paramagnetic resonance spectroscopy identified a 2N1S1O coordination to the Cu(2+) atom, suggesting histidine 111 and methionine 109 or 112 are involved. Nuclear magnetic resonance confirmed Cu(2+) and Zn(2+) binding to His-111 and weaker binding to Met-112. An N-terminally acetylated PrP106-126 peptide did not bind Cu(2+), implicating the free amino group in metal binding. Mutagenesis of either His-111, Met-109, or Met-112 abolished PrP106-126 neurotoxicity and its ability to form fibrils. Therefore, Cu(2+) and/or Zn(2+) binding is critical for PrP106-126 aggregation and neurotoxicity.

History

Journal

Biochemistry

Volume

40

Issue

27

Pagination

8073 - 8084

Publisher

American Chemical Society

Location

Washington, D.C.

ISSN

0006-2960

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2001, American Chemical Society