Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology
Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology
复制标题
DOI：
10.1021/jp2108126
复制
发表时间：
2012-02-09
影响因子：
3.3
通讯作者：
Lal, Ratnesh
中科院分区：
文献类型：
--
作者：
Connelly, Laura;Jang, Hyunbum;Lal, Ratnesh
阿尔茨海默病（AD）是一种蛋白质错误折叠疾病，其特征在于β-淀粉样蛋白（A β）肽积聚为老年斑、不受控制的神经变性和记忆丧失。AD病理学与细胞离子稳态的不稳定有关，并且涉及A β肽-质膜相互作用。原则上，有两种可能的方式可以发生离子稳态的干扰：直接地，其中A β肽插入膜中并产生离子传导孔或使膜组织不稳定，或者间接地，其中A β肽与现有的细胞膜受体相互作用。为了区分这两种可能的A β-膜相互作用类型，我们利用了配体-受体相互作用具有立体特异性的生化原理; L-氨基酸肽，而不是它们的D-对应物，与细胞膜受体结合。然而，就离子通道介导的机制而言，与L-氨基酸一样，D-氨基酸肽也会形成离子通道样结构。使用原子力显微镜（AFM），我们成像的D-和L-对映体的全长A β（1-42）的结构时，在脂质双层重构。AFM成像显示，L-和D-A β异构体形成类似的通道样结构。分子动力学（MD）模拟支持AFM成像的3D结构。以前，我们已经表明，D-A β（1-42）通道传导离子类似于它们的L-对应物。总而言之，我们的结果支持A β离子通道介导的离子稳态不稳定的直接机制，而不是通过A β与膜受体相互作用的间接机制。
Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of beta-amyloid (A beta) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves A beta peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the A beta peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the A beta peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of A beta-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length A beta(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-A beta isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-A beta(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of A beta ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through A beta interaction with membrane receptors.