Document Detail

Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits.
MedLine Citation:
PMID:  11274207     Owner:  NLM     Status:  MEDLINE    
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.
C C Curtain; F Ali; I Volitakis; R A Cherny; R S Norton; K Beyreuther; C J Barrow; C L Masters; A I Bush; K J Barnham
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-03-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-04     Completed Date:  2001-07-12     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20466-73     Citation Subset:  IM    
Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria 3052, Australia.
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MeSH Terms
Allosteric Regulation
Alzheimer Disease / metabolism*
Amyloid beta-Protein / metabolism*
Cell Membrane / metabolism
Circular Dichroism
Copper / metabolism*
Electron Spin Resonance Spectroscopy
Nuclear Magnetic Resonance, Biomolecular
Protein Binding
Spin Labels
Superoxide Dismutase / chemistry,  metabolism*
Zinc / metabolism*
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Spin Labels; 7440-50-8/Copper; 7440-66-6/Zinc; EC Dismutase

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