Antiparallel β-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-β Peptides When They Form 150-kDa Oligomers.
Antiparallel β-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-β Peptides When They Form 150-kDa Oligomers.
复制标题
DOI：
10.1016/j.jmb.2015.04.004
复制
发表时间：
2015-07-03
影响因子：
5.6
通讯作者：
Paravastu, Anant K.
中科院分区：
文献类型：
--
作者：
Huang, Danting;Zimmerman, Maxwell I.;Martin, Patricia K.;Nix, A. Jeremy;Rosenberry, Terrone L.;Paravastu, Anant K.
了解淀粉样蛋白-β(A-β)低聚体的分子结构和潜在的组装途径将在分子水平上促进我们对阿尔茨海默病(AD)的理解。这一认识有助于疾病的预防、诊断和治疗策略，因为寡聚体在AD病理中起着核心作用。我们最近提出了一种与固体核磁共振分析相兼容的150 kDa Aβ(1-42)寡聚样品(Aβ肽的42个残基变体)的制备方法，并且我们已经证明这些低聚物和淀粉样纤维在β链的分子间排列上是不同的。在这里，我们报告了新的固态核磁共振限制条件，表明低聚物中β链的反平行分子间排列。具体地说，在I32、M35、G37和V40具有统一的13C和15N同位素标记的150 kDa Aβ(1-42)低聚物在2D fpRFDR核磁共振谱中显示出β链二级化学位移，在2D Darr谱中表现出I32和V40以及M35和G37之间的空间邻近，在2D CHHC谱中M35 Hα和G37 Hα非常接近。此外，对用30%标记多肽制备的齐聚物样品的2D DAR分析表明，I32-V40和M35-G37是在不同分子上的残基之间接触的。我们使用分子模拟来比较新得到的实验约束条件与以前提出的将Aβ分子排列成低聚物的几何构型。
Understanding the molecular structures of amyloid-β (Aβ) oligomers and underlying assembly pathways will advance our understanding of Alzheimer’s disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, and treatment strategies, as oligomers play a central role in AD pathology. We have recently presented a procedure for production of 150 kDa oligomeric samples of Aβ(1–42) (the 42-residue variant of the Aβ peptide) that are compatible with solid state NMR analysis, and we have shown that these oligomers and amyloid fibrils differ in intermolecular arrangement of β-strands. Here we report new solid state NMR constraints that indicate antiparallel intermolecular alignment of β-strands within the oligomers. Specifically, 150 kDa Aβ(1–42) oligomers with uniform 13C and 15N isotopic labels at I32, M35, G37 and V40 exhibit β-strand secondary chemical shifts in 2D fpRFDR NMR spectra, spatial proximities between I32 and V40 as well as between M35 and G37 in 2D DARR spectra, and close proximity between M35 Hα and G37 Hα in 2D CHHC spectra. Furthermore, 2D DARR analysis of an oligomer sample prepared with 30% labeled peptide indicates that the I32-V40 and M35-G37 contacts are between residues on different molecules. We employ molecular modeling to compare the newly derived experimental constraints with previously proposed geometries for arrangement of Aβ molecules into oligomers.
登录
查看更多内容
影响因子：
4.4
作者：
Ishii, Y
通讯作者：
Ishii, Y
影响因子：
4.8
作者：
Gu, Lei;Liu, Cong;Guo, Zhefeng
通讯作者：
Guo, Zhefeng
DOI：
10.1073/pnas.0703793104
发表时间：
2007-12-04
影响因子：
11.1
作者：
Habicht, Gernot;Haupt, Christian;Faendrich, Marcus
通讯作者：
Faendrich, Marcus
影响因子：
2.9
作者：
Nichols, MR;Moss, MA;Rosenberry, TL
通讯作者：
Rosenberry, TL
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH