Activity and Architecture of Pyroglutamate-Modified Amyloid-尾 (A尾pE3-42) Pores

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• 作者：Alan L. Gillman ; Hyunbum Jang ; Joon Lee ; Srinivasan Ramachandran ; Bruce L. Kagan ; Ruth Nussinov ; Fernando Teran Arce
• 刊名：Journal of Physical Chemistry B
• 出版年：2014
• 出版时间：July 3, 2014
• 年：2014
• 卷：118
• 期：26
• 页码：7335-7344
• 全文大小：583K
• ISSN：1520-5207

文摘

Among the family of A尾 peptides, pyroglutamate-modified A尾 (A尾<sub>pEsub>) peptides are particularly associated with cytotoxicity in Alzheimer鈥檚 disease (AD). They represent the dominant fraction of A尾 oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of A尾<sub>pEsub> plaques precedes the formation of plaques of full-length A尾 (A尾<sub>1-40/42sub>). Most of these properties appear to be associated with the higher hydrophobicity of A尾<sub>pEsub> as well as an increased resistance to enzymatic degradation. However, the important question of whether A尾<sub>pEsub> peptides induce pore activity in lipid membranes and their potential toxicity compared with other A尾 pores is still open. Here we examine the activity of A尾<sub>pEsub> pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that A尾<sub>pEsub> pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the A尾 family. However, there are also some significant differences. The onset of A尾<sub>pE3-42sub> pore activity is generally delayed compared with A尾<sub>1-42sub> pores. However, once formed, A尾<sub>pE3-42sub> pores produce increased ion permeability of the membrane, as indicated by a greater occurrence of higher conductance electrical events. Structurally, the lactam ring of A尾<sub>pEsub> peptides induces a change in the conformation of the N-terminal strands of the A尾<sub>pE3-42sub> pores. While the N-termini of wild-type A尾<sub>1鈥?2sub> peptides normally reside in the bulk water region, the N-termini of A尾<sub>pE3-42sub> peptides tend to reside in the hydrophobic lipid core. These studies provide a first step to an understanding of the enhanced toxicity attributed to A尾<sub>pEsub> peptides.