Physical Chemistry, Eidgenössische Technische Hochschule Zürich Zurich, Switzerland.
Institut de Biologie et Chimie des Protéines, Bases Moléculaires et Structurales des Systèmes Infectieux, Labex Ecofect, UMR 5086 CNRS, Université de Lyon Lyon, France.
Front Mol Biosci. 2015 Apr 28;2:14. doi: 10.3389/fmolb.2015.00014. eCollection 2015.
Recently the 3D structure of the Osaka mutant form (E22Δ) of Amyloid-β1-40 has been determined. We here compare the NMR chemical-shift with the published shifts of a brain-seeded form of wild-type Aβ and suggest that the determined mutant fold is accessible to the wild-type protein as well, with small conformational adaptations which accommodate the E22 residue missing in the Osaka mutant. In addition, we illustrate how other mutants could also conform to this model. The stabilization of the N-terminal part of the protein via an intermolecular salt bridge to Lys28 may represent a common structural motif for the mutants which are related to early-onset Alzheimer disease. This feature might connect to the observed increased toxicity of the mutant forms compared to wild-type Aβ1-40, where the salt bridge involving Lys28 is intramolecular.
最近，大阪突变体形式（E22Δ）的淀粉样蛋白-β1-40 的 3D 结构已经确定。我们在这里将 NMR 化学位移与野生型 Aβ 的脑种子形式的已发表位移进行比较，并提出该确定的突变折叠也可以被野生型蛋白获得，只需进行小的构象适应以容纳在大阪突变体中缺失的 E22 残基。此外，我们还说明了其他突变体如何也能符合这一模型。通过与 Lys28 形成的分子间盐桥稳定蛋白质的 N 端部分可能代表与早发性阿尔茨海默病相关的突变体的共同结构基序。这一特征可能与突变体形式与野生型 Aβ1-40 相比观察到的毒性增加有关，其中涉及 Lys28 的盐桥是分子内的。
