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Alzheimer's disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits

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posted on 2001-06-08, 00:00 authored by C C Curtain, F Ali, I Volitakis, R A Cherny, R S Norton, K Beyreuther, Colin BarrowColin Barrow, C L Masters, A I Bush, K J Barnham
Amyloid beta peptide (Abeta) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Cu(2+) and Zn(2+) bind Abeta, inducing aggregation and giving rise to reactive oxygen species. These reactions may play a deleterious role in the disease state, because high concentrations of iron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to Abeta is the same in both aqueous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu(2+)/peptide molar ratios >0.3, Abeta coordinated a second Cu(2+) atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at N(epsilon)2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase. Addition of Cu(2+) or Zn(2+) to Abeta in a negatively charged lipid environment caused a conformational change from beta-sheet to alpha-helix, accompanied by peptide oligomerization and membrane penetration. These results suggest that metal binding to Abeta generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.

History

Journal

Journal of biological chemistry

Volume

276

Issue

23

Pagination

20466 - 20473

Publisher

American Society for Biochemistry and Molecular Biology

Location

Bethesda, Md.

ISSN

0021-9258

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2001, American Society for Biochemistry and Molecular Biology