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首页> 外文期刊>Journal of Molecular Biology >Molecular Origins of the Compatibility between Glycosaminoglycans and A beta 40 Amyloid Fibrils
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Molecular Origins of the Compatibility between Glycosaminoglycans and A beta 40 Amyloid Fibrils

机译：糖胺聚糖与β40淀粉样蛋白原纤维之间的相容性的分子起源

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The A beta peptide forms extracellular plaques associated with Alzheimer's disease. In addition to protein fibrils, amyloid plaques also contain non-proteinaceous components, including glycosaminoglycans (GAGs). We have shown previously that the GAG low-molecular-weight heparin (LMWH) binds to A beta 40 fibrils with a three-fold-symmetric (3Q) morphology with higher affinity than A beta 40 fibrils in alternative structures, A beta 42 fibrils, or amyloid fibrils formed from other sequences. Solid-state NMR analysis of the GAG-3Q fibril complex revealed an interaction site at the corners of the 3Q fibril structure, but the origin of the binding specificity remained obscure. Here, using a library of short heparin polysaccharides modified at specific sites, we show that the N-sulfate or 6-0-sulfate of glucosamine, but not the 2-0-sulfate of iduronate within heparin is required for 3Q binding, indicating selectivity in the interactions of the GAG with the fibril that extends beyond general electrostatic complementarity. By creating 3Q fibrils containing point substitutions in the amino acid sequence, we also show that charged residues at the fibril three-fold apices provide the majority of the binding free energy, while charged residues elsewhere are less critical for binding. The results indicate, therefore, that LMWH binding to 3Q fibrils requires a precise molecular complementarity of the sulfate moieties on the GAG and charged residues displayed on the fibril surface. Differences in GAG binding to fibrils with distinct sequence and/or structure may thus contribute to the diverse etiology and progression of amyloid diseases. (C) 2017 The Authors. Published by Elsevier Ltd.
机译：β肽形成与阿尔茨海默病相关的细胞外斑块。除蛋白质原纤维外，淀粉样蛋白斑块还含有非蛋白质组分，包括糖胺聚糖（GAG）。我们以前表明，GAG低分子量肝素（LMWH）与β40原纤维结合，具有三倍对称（3Q）形态，其亲和力比替代结构中的β40原纤维更高，β22原纤维，或由其他序列形成的淀粉样蛋白原纤维。 GAG-3Q原纤维复合物的固态NMR分析显示了3Q原纤维结构的拐角处的相互作用位点，但结合特异性的起源仍然模糊不清。在此，使用在特定位点改性的短肝素多糖文库，我们表明3Q结合需要血糖胺的正硫酸n或6-0-硫酸胍，但不需要在肝素内雌磺酸盐的2-0-硫酸盐，表明选择性在GAG与纤维的相互作用中，其延伸超出一般静电互补性。通过在氨基酸序列中含有点取代的3Q原纤维，我们还表明，原纤维的带电残余物三倍的夹子的带电残基提供了大部分的无结合能量，而其他地方的带电残留物对结合不太关键。因此，结果表明，与3Q原纤维结合的LMWH结合需要在胶原上的硫酸盐部分的精确分子互补性和在原纤维表面上显示的带电残余物。因此，具有不同序列和/或结构的原纤维的GAG的差异可以有助于淀粉样疾病的不同病因和进展。 （c）2017年作者。 elsevier有限公司出版

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