β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.
β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.
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DOI：
10.1021/acs.biochem.3c00526
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发表时间：
2024-01-16
期刊：
影响因子：
2.9
通讯作者：
Nowick, James S.
中科院分区：
文献类型：
--
作者：
Ruttenberg, Sarah M.;Kreutzer, Adam G.;Truex, Nicholas L.;Nowick, James S.
β 淀粉样蛋白 (Aβ) 形成异质寡聚体，与阿尔茨海默病 (AD) 的发病机制有关。许多 Aβ 寡聚物由 β-发夹结构单元 — β-发夹构象的 Aβ 肽组成。 Aβ的β-发夹可以采用多种排列方式，但β-发夹排列在Aβ寡聚体的形成和异质性中所起的作用知之甚少。为了探索β-发夹排列对Aβ肽寡聚化的影响，我们设计并研究了具有两种不同β-发夹排列的两种模型肽。肽 Aβm17-36 和 Aβm17-35 模拟 Aβ 可以形成的两种不同的 β-发夹，分别是 Aβ17-36 和 Aβ17-35 β-发夹。这些发夹结构相似，但发夹排列不同，改变了它们所含残基侧链的面部排列。 X 射线晶体学和 SDS-PAGE 证明这些肽之间的面部排列差异导致不同的寡聚物形成。在晶体状态下，Aβm17-36 形成三角形三聚体，进一步组装形成六聚体，而 Aβm17-35 形成四聚体 β-桶。在 SDS-PAGE 中，Aβm17-36 组装形成寡聚体梯，而 Aβm17-35 组装形成二聚体或根本不组装。 Aβm17-36 和 Aβm17-35 行为的差异表明 β-发夹排列是观察到的 Aβ 寡聚物异质性的来源。
Amyloid-β (Aβ) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer’s disease (AD). Many Aβ oligomers consist of β-hairpin building blocks—Aβ peptides in β-hairpin conformations. β-Hairpins of Aβ can adopt a variety of alignments, but the role that β-hairpin alignment plays in the formation and heterogeneity of Aβ oligomers is poorly understood. To explore the effect of β-hairpin alignment on the oligomerization of Aβ peptides, we designed and studied two model peptides with two different β-hairpin alignments. Peptides Aβm17–36 and Aβm17–35 mimic two different β-hairpins that Aβ can form, the Aβ17–36 and Aβ17–35 β-hairpins, respectively. These hairpins are similar in composition but differ in hairpin alignment, altering the facial arrangements of the side chains of the residues that they contain. X-ray crystallography and SDS-PAGE demonstrate that the difference in facial arrangement between these peptides leads to distinct oligomer formation. In the crystal state, Aβm17–36 forms triangular trimers that further assemble to form hexamers, while Aβm17–35 forms tetrameric β-barrels. In SDS-PAGE, Aβm17–36 assembles to form a ladder of oligomers, while Aβm17–35 either assembles to form a dimer or does not assemble at all. The differences in the behavior of Aβm17–36 and Aβm17–35 suggest β-hairpin alignment as a source of the observed heterogeneity of Aβ oligomers.
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影响因子：
2.9
作者：
McKnelly, Kate J.;Kreutzer, Adam G.;Howitz, William J.;Haduong, Katelyn;Yoo, Stan;Hart, Candace;Nowick, James S.
通讯作者：
Nowick, James S.
影响因子：
2.7
作者：
Jarvet, Jueri;Danielsson, Jens;Graeslund, Astrid
通讯作者：
Graeslund, Astrid
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
5
作者：
Kreutzer AG;Samdin TD;Guaglianone G;Spencer RK;Nowick JS
通讯作者：
Nowick JS
影响因子：
18.3
作者：
Kreutzer AG;Nowick JS
通讯作者：
Nowick JS