Investigations of the Molecular Mechanism of Metal-Induced A (1-40) Amyloidogenesis
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- 作者：Kwang Hun Lim ; Yun Kyung Kim ; Young-Tae Chang
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：November 27, 2007
- 年：2007
- 卷：46
- 期：47
- 页码：13523 - 13532
- 全文大小：430K
- 年卷期：v.46,no.47(November 27, 2007)
- ISSN：1520-4995
文摘
Transition-metal ions (Cu2+ and Zn2+) play critical roles in the A plaque formation. However,precise roles of the metal ions in the A amyloidogenesis have been controversial. In this study, themolecular mechanism of the metal-induced A oligomerization was investigated with extensive metalion titration NMR experiments. Upon additions of the metal ions, the N-terminal region (1-16) of theA (1-40) peptide was selectively perturbed. In particular, polar residues 4-8 and 13-15 were morestrongly affected by the metal ions, suggesting that those regions may be the major binding sites of themetal 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 facilitatethe intermolecular contact between the A peptides. The A (1-40) peptides (>30 M) were eventuallyoligomerized even at low temperature (3 C), where the A peptides are stable as monomeric formswithout the metal ions. The real-time oligomerization process was monitored by 1H/15N HSQC NMRexperiments, which provided the first residue-specific structural transition information. Hydrophobic residues12-21 initially underwent conformational changes due to the intermolecular interactions. After the initialstructural rearrangements, the C-terminal residues (32-40) readjusted their conformations presumablyfor effective oligomerization. Similar structural changes of the metal-free A (1-40) peptides were alsoobserved in the presence of the preformed oligomers, suggesting that the conformational transitions maybe the general molecular mechanism of the A (1-40) amyloidogenesis.