Journal
BIOCHEMISTRY
Volume 46, Issue 47, Pages 13523-13532Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi701112z
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Transition-metal ions (Cu2+ and Zn2+) play critical roles in the A beta plaque formation. However, precise roles of the metal ions in the A beta amyloidogenesis have been controversial. In this study, the molecular mechanism of the metal-induced A beta oligomerization was investigated with extensive metal ion titration NMR experiments. Upon additions of the metal ions, the N-terminal region (1-16) of the A beta (1-40) peptide was selectively perturbed. In particular, polar residues 4-8 and 13-15 were more strongly affected by the metal ions, suggesting that those regions may be the major binding sites of the metal ions. The NMR signal changes of the N-terminal region were dependent on the peptide concentrations (higher peptide concentrations resulted in stronger signal changes), suggesting that the metal ions facilitate the intermolecular contact between the A beta peptides. The A beta (1-40) peptides (> 30 mu M) were eventually oligomerized even at low temperature (3 degrees C), where the A beta peptides are stable as monomeric forms without the metal ions. The real-time oligomerization process was monitored by H-1/N-15 HSQC NMR experiments, which provided the first residue-specific structural transition information. Hydrophobic residues 12-21 initially underwent conformational changes due to the intermolecular interactions. After the initial structural rearrangements, the C-terminal residues (32-40) readjusted their conformations presumably for effective oligomerization. Similar structural changes of the metal-free A beta (1-40) peptides were also observed in the presence of the preformed oligomers, suggesting that the conformational transitions may be the general molecular mechanism of the A beta (1-40) amyloidogenesis.
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