[Conformational regulation of amyloid beta-peptide by lipid membranes and metal ions].
Conformational transition of monomeric amyloid beta-peptide (Abeta) to a self-associated beta-sheet structure is considered to be an initial step in the development of Alzheimer's disease. Several lines of evidence suggest that physiologically abundant lipid membranes and metal ions are involved in this step. We have demonstrated that Abeta binds to the phosphatidylcholine membrane in the lamellar gel phase but not in the liquid crystalline phase by using fluorescence and circular dichroism spectroscopy. The membrane-bound Abeta molecule takes alpha-helical or beta-sheet structure depending on the temperature. Tightly packed phosphatidylcholine membranes appear to serve as a platform for non-electrostatic binding and self-association of Abeta. We have also examined Zn(II) and Cu(II) binding modes of Abeta by Raman spectroscopy. The Raman spectra demonstrate that three histidine residues in the N-terminal region of Abeta provide primary metal binding sites. Zn(II) binds to the N(tau) atom of histidine and the peptide aggregates through intermolecular His-Zn-His bridges. In contrast, Cu(II) ion is chelated by the N(pi) atom of histidine and deprotonated main-chain amide nitrogens to form a soluble complex. Our findings on the conformational regulation of Abeta may help in better understanding the molecular basis for the development of Alzheimer's disease.
Miura
Takashi
T
Tohoku University, Sendai, Japan. tmiura@mail.pharm.tohoku.ac.jp
Yoda
Mayumi
M
Tsutsumi
Chihiro
C
Murayama
Kiyoko
K
Takeuchi
Hideo
H
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001665:Binding Sites; D003300:Copper / Q000378:metabolism*; D006801:Humans; D007477:Ions; D008563:Membrane Lipids / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013059:Spectrum Analysis, Raman; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007477:Ions; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D003300:Copper; D015032:Zinc