Nature and significance of the interactions between amyloid fibrils and biological polyelectrolytes
Nature and significance of the interactions between amyloid fibrils and biological polyelectrolytes
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DOI：
10.1021/bi0610653
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发表时间：
2006-10-24
期刊：
影响因子：
2.9
通讯作者：
Dobson, Christopher M.
中科院分区：
文献类型：
--
作者：
Calamai, Martino;Kumita, Janet R.;Dobson, Christopher M.
带电荷的聚电解质如糖胺聚糖和核酸经常被发现与淀粉样疾病患者组织中的蛋白质沉积有关。我们通过研究不同聚阴离子（包括DNA、ATP、肝素和硫酸乙酰肝素）促进淀粉样蛋白聚集并与所得聚集体结合的能力，研究了这种现象的性质和普遍性。人肌肉酰基磷酸酶和人溶菌酶的预形成淀粉样纤维，在生理pH值下具有净正电荷的蛋白质，被发现与带负电荷的DNA或ATP紧密结合。聚电解质对聚集动力学的影响进行了研究，为酰基磷酸酶，ATP，DNA，或肝素的存在下，发现增加其聚集率显着，与依赖于净电荷和大小的聚阴离子的程度。镁或钙离子被发现衰减，并最终抑制，这些相互作用，这表明它们是静电的性质。此外，肝素被发现通过静电排斥的补偿稳定的酰基磷酸酶的聚集状态。值得注意的是，天然和聚集的酰基磷酸酶与肝素之间的亲和力差异表明，淀粉样蛋白原纤维本身可以表现为聚电解质，与其他带有相反电荷的聚电解质相互作用非常强烈。在体内环境中，由于蛋白质错误折叠和聚集，与其他生物聚电解质的静电相互作用的加强，因此可能导致必需分子组分的耗尽，并导致淀粉样蛋白原纤维及其前体的已知细胞毒性。
Charged polyelectrolytes such as glycosaminoglycans and nucleic acids have frequently been found associated with the proteinaceous deposits in the tissues of patients with amyloid diseases. We have investigated the nature and generality of this phenomenon by studying the ability of different polyanions, including DNA, ATP, heparin, and heparan sulfate, to promote the aggregation of amyloidogenic proteins and to bind to the resulting aggregates. Preformed amyloid fibrils of human muscle acylphosphatase and human lysozyme, proteins with a net positive charge at physiological pH values, were found to bind tightly to the negatively charged DNA or ATP. The effects of the polyelectrolytes on the kinetics of aggregation were studied for acylphosphatase, and the presence of ATP, DNA, or heparin was found to increase its aggregation rate dramatically, with a degree dependent on the net charge and size of the polyanion. Magnesium or calcium ions were found to attenuate, and ultimately to suppress, these interactions, suggesting that they are electrostatic in nature. Moreover, heparin was found to stabilize the aggregated state of acylphosphatase through compensation of electrostatic repulsion. Noteworthy, differences in affinity between native and aggregated acylphosphatase with heparin suggest that amyloid fibrils can themselves behave as polyelectrolytes, interacting very strongly with other polyelectrolytes bearing the opposite charge. Within an in vivo context, the strengthening of the electrostatic interactions with other biological polyelectrolytes, as a consequence of protein misfolding and aggregation, could therefore result in depletion of essential molecular components and contribute to the known cytotoxicity of amyloid fibrils and their precursors.