Dulin Fabienne, Callebaut Isabelle, Colloc'h Nathalie, Mornon Jean-Paul
Département de Biologie Structurale, IMPMC, CNRS UMR7590, Universités Pierre et Marie Curie-Paris 6 et Denis Diderot-Paris 7, F-75005 France.
Biopolymers. 2007;85(5-6):422-37. doi: 10.1002/bip.20675.
Abeta fibrils, which are central to the pathology of Alzheimer's disease, form a cross-beta-structure that contains likely parallel beta-sheets with a salt bridge between residues Asp23 and Lys28. Recent studies suggest that soluble oligomers of amyloid peptides have neurotoxic effects in cell cultures, raising the interest in studying the structures of these intermediate forms. Here, we present three models of possible soluble Abeta forms based on the sequences similarities, assumed to support local structural similarities, of the Abeta peptide with fragments of three proteins (adhesin, Semliki Forest virus capsid protein, and transthyretin). These three models share a similar structure in the C-terminal region composed of two beta-strands connected by a loop, which contain the Asp23-Lys28 salt bridge. This segment is also structurally well conserved in Abeta fibril forms. Differences between the three monomeric models occur in the N-terminal region and in the C-terminal tail. These three models might sample some of the most stable conformers of the soluble Abeta peptide within oligomeric assemblies, which were modeled here in the form of dimers, trimers, tetramers, and hexamers. The consistency of these models is discussed with respect to available experimental and theoretical data.
β淀粉样蛋白纤维是阿尔茨海默病病理学的核心，它形成了一种交叉β结构，其中包含可能平行的β折叠片层，在天冬氨酸23和赖氨酸28残基之间有一个盐桥。最近的研究表明，淀粉样肽的可溶性寡聚体在细胞培养中具有神经毒性作用，这引发了对研究这些中间形式结构的兴趣。在此，我们基于β淀粉样肽与三种蛋白质（粘附素、辛德毕斯病毒衣壳蛋白和转甲状腺素蛋白）片段的序列相似性（假定支持局部结构相似性），提出了三种可能的可溶性β淀粉样蛋白形式的模型。这三种模型在由一个环连接的两条β链组成的C末端区域具有相似的结构，该区域包含天冬氨酸23 - 赖氨酸28盐桥。该片段在β淀粉样蛋白纤维形式中在结构上也高度保守。三种单体模型之间的差异出现在N末端区域和C末端尾部。这三种模型可能代表了可溶性β淀粉样肽在寡聚体组装体中一些最稳定的构象，这里以二聚体、三聚体、四聚体和六聚体的形式对其进行了建模。我们根据现有的实验和理论数据讨论了这些模型的一致性。
