Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
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DOI：
10.1038/nsmb.2991
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发表时间：
2015-06
影响因子：
16.8
通讯作者：
Ishii, Yoshitaka
中科院分区：
文献类型：
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作者：
Xiao, Yiling;Ma, Buyong;McElheny, Dan;Parthasarathy, Sudhakar;Long, Fei;Hoshi, Minako;Nussinov, Ruth;Ishii, Yoshitaka
越来越多的证据表明，42个残基的人淀粉样蛋白β（Aβ（1-42））的错误折叠聚集体的形成和繁殖，而不是更丰富的Aβ（1-40），引发阿尔茨海默氏症级联反应。迄今为止，错误折叠的Aβ（1-42）的结构细节仍然难以捉摸。本文基于固体核磁共振（SSNMR）数据，提出了Aβ（1-42）淀粉样纤维的原子模型。它显示了三重平行β折叠片段，与报道的Aβ（1-40）原纤维结构不同。值得注意的是，Aβ（1-40）与三重-β基序不相容，因为用Aβ（1-42）原纤维接种不会促进单体Aβ（1-40）通过交叉复制转化为原纤维。SSNMR实验表明，Aβ（1-40）中不存在的Ala 42羧基端与Lys 28形成盐桥，作为排除Aβ（1-40）的自识别分子开关。结果提供了对早期阿尔茨海默病中Aβ（1-42）选择性自我复制淀粉样蛋白传播机制的深入了解。
Increasing evidence suggests that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1–42)), rather than the more abundant Aβ(1–40), provokes the Alzheimer’s cascade. To date, structural details of misfolded Aβ(1–42) have remained elusive. Here we present the atomic model of Aβ(1–42) amyloid fibril based on solid-state NMR (SSNMR) data. It displays triple parallel-β-sheet segments that are different from reported structures of Aβ(1–40) fibrils. Remarkably, Aβ(1–40) is not compatible with the triple-β motif, as seeding with Aβ(1–42) fibrils does not promote conversion of monomeric Aβ(1–40) into fibrils via cross-replication. SSNMR experiments suggest that the Ala42 carboxyl terminus, absent in Aβ(1–40), forms a salt-bridge with Lys28 as a self-recognition molecular switch that excludes Aβ(1–40). The results provide insight into Aβ(1–42)-selective self-replicating amyloid propagation machinery in early-stage Alzheimer’s disease.
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影响因子：
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作者：
Chimon, S;Ishii, Y
通讯作者：
Ishii, Y
影响因子：
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作者：
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