Probing the role of backbone hydrogen bonding in β-amyloid fibrils with inhibitor peptides containing ester bonds at alternate positions
Probing the role of backbone hydrogen bonding in β-amyloid fibrils with inhibitor peptides containing ester bonds at alternate positions
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DOI：
10.1021/bi0259857
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发表时间：
2003-01-21
期刊：
影响因子：
2.9
通讯作者：
Meredith, SC
中科院分区：
文献类型：
--
作者：
Gordon, DJ;Meredith, SC
蛋白质之间的相互作用通常由稳定的、分子间的β-折叠来调节。例如，许多细胞因子和HIV蛋白酶通过β-折叠基序二聚化。证据还表明，淀粉样纤维中的多肽和蛋白质的大分子组装是由分子间的β-折叠稳定的。在这篇文章中，我们报道了通过用酯键取代酰胺键来干扰淀粉样蛋白多肽(Abeta16-20)的主干氢键，阻止了多肽的聚集。酯键以交替的方式结合，因此当以延伸的β-链构象排列时，肽呈现两个独特的氢键面；肽的一个面具有正常的氢键能力，但另一个面缺少酰胺质子，其氢键能力受到严重限制。分析超速离心实验表明，这种酯肽，Abeta16-20e，在溶液条件下主要是单体，不同于形成纤维的Abeta16-20肽。Abeta16-20e还抑制Abeta1-40肽的聚集，并分解预先形成的Abeta1-40纤维。这些结果表明，骨架氢键对淀粉样蛋白纤维的组装至关重要。
Protein-protein interactions are frequently mediated by stable, intermolecular beta-sheets. A number of cytokines and the HIV Protease, for example, dimerize through beta-sheet motifs. Evidence also suggests that the macromolecular assemblies of peptides and proteins in amyloid fibrils are stabilized by intermolecular beta-sheets. In this paper, we report that interfering with the backbone hydrogen bonding of an amyloidgenic peptide (Abeta16-20) by replacing amide bonds with ester bonds prevents the aggregation of the peptide. The ester bonds were incorporated in an alternating fashion so that the peptide presents two unique hydrogen bonding faces when arrayed in an extended, beta-strand conformation; one face of the peptide has normal hydrogen bonding capabilities, but the other face is missing amide protons and its ability to hydrogen bond is severely limited. Analytical ultracentrifugation experiments demonstrate that this ester peptide, Abeta16-20e, is predominantly monomeric under solution conditions, unlike the fibril-forming Abeta16-20 peptide. Abeta16-20e also inhibits the aggregation of the Abeta1-40 peptide and disassembles preformed Abeta1-40 fibrils. These results suggest that backbone hydrogen bonding is critical for the assembly of amyloid fibrils.