Investigations of the molecular mechanism of metal-induced A beta (1-40) amyloidogenesis
SCIE
SCOPUS
- Title
- Investigations of the molecular mechanism of metal-induced A beta (1-40) amyloidogenesis
- Authors
- Lim, Kwang Hun; Kim, Yun Kyung; Chang, Young-Tae
- Date Issued
- 2007-11
- Publisher
- AMER CHEMICAL SOC
- Abstract
- Transition-metal ions (Cu(2+) and Zn(2+)) 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 (1)H/(15)N 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.
- Keywords
- AMYLOID-BETA; ALZHEIMERS-DISEASE; COPPER-BINDING; IN-VITRO; EXPERIMENTAL CONSTRAINTS; PROTEIN OLIGOMERIZATION; CU(II) POTENTIATION; INDUCED AGGREGATION; SECONDARY STRUCTURE; HYDROGEN-PEROXIDE
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/50251
- DOI
- 10.1021/bi701112z
- ISSN
- 0006-2960
- Article Type
- Article
- Citation
- BIOCHEMISTRY, vol. 46, no. 47, page. 13523 - 13532, 2007-11
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