Ca2+ Interacts with Glu-22 of A尾(1鈥?2) and Phospholipid Bilayers to Accelerate the A尾(1鈥?2) Aggregation Below the Critical Micelle Concentration

详细信息    查看全文

• 作者：Xinyao Yi ; Yi Zhang ; Ming Gong ; Xiang Yu ; Narek Darabedian ; Jie Zheng ; Feimeng Zhou
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：October 20, 2015
• 年：2015
• 卷：54
• 期：41
• 页码：6323-6332
• 全文大小：419K
• ISSN：1520-4995

文摘

The amyloid cascade hypothesis links the amyloid-尾 (A尾) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer鈥檚 disease (AD). Although A尾 aggregation has been known to accelerate at cell membranes, the exact mechanism of A尾 peptide deposition and the involvement of extracellular species are still largely unclear. Using surface plasmon resonance (SPR) and atomic force microscopy (AFM), we demonstrate that Ca²⁺ ions, in conjunction with lipid bilayer, lower the threshold concentration for A尾 aggregation (>a few micromolar in vitro) to physiological levels (low nanomolar). Circular dichroism spectroscopy reveals that Ca²⁺ ions and the lipid bilayer concertedly accelerate the conformational change or misfolding of A尾 peptides. Molecular dynamics calculation indicates that Ca²⁺ is sandwiched between Glu-22 of A尾 and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca²⁺, A尾(1鈥?2), and the phospholipid bilayer. With the C- and N-termini of the A尾 dimer fully exposed for the attachment of additional A尾 molecules, fibrils formed with the Ca²⁺-anchored A尾 nuclei appear to interact with lipid bilayers differently from those preformed in solution. Thus, similar to the role of Ca²⁺ in enriching islet amyloid polypeptides in the pancreas of diabetic patients ( Biophys. J. 2013, 104, 173鈭?84) and the 鈥淐a²⁺ bridge鈥?in mediating membrane interaction with 伪-synuclein in the Parkinson鈥檚 disease ( Biochemistry, 2006, 45, 10947鈭?0956), the influence of Ca²⁺ on the A尾 adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked.