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首页> 外文期刊>Biochemistry >Sulfated Glycosaminoglycans Accelerate Transthyretin Amyloidogenesis by Quaternary Structural Conversion
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Sulfated Glycosaminoglycans Accelerate Transthyretin Amyloidogenesis by Quaternary Structural Conversion

机译：硫酸糖胺聚糖通过四级结构转化促进甲状腺素转运蛋白的淀粉样蛋白生成。

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摘要

Glycosaminoglycans (GAGs), which are found in association with all extracellular amyloid deposits in humans, are known to accelerate the aggregation of various amyloidogenic proteins in vitro. However, the precise molecular mechanism(s) by which GAGs accelerate amyloidogenesis remains elusive. Herein, we show that sulfated GAGs, especially heparin, accelerate transthyretin (TTR) amyloidogenesis by quaternary structural conversion. The clustering of sulfate groups on heparin and its polymeric nature are essential features for accelerating TTR amyloidogenesis. Heparin does not influence TTR tetramer stability or TTR dissociation kinetics, nor does it alter the folded monomer-misfolded monomer equilibrium directly. Instead, heparin accelerates the conversion of preformed TTR oligomers into larger aggregates. The more rapid disappearance of monomeric TTR in the presence of heparin likely reflects the fact that the monomer-misfolded amyloidogenic monomer-oligomer-TTR fibril equilibria are all linked, a hypothesis that is strongly supported by the light scattering data. TTR aggregates prepared in the presence of heparin exhibit a higher resistance to trypsin and proteinase K proteolysis and a lower exposure of hydrophobic side chains comprising hydrophobic clusters, suggesting an active role for heparin in amyloidogenesis. Our data suggest that heparin accelerates TTR aggregation by a scaffold-based mechanism, in which the sulfate groups comprising GAGs interact primarily with TTR oligomers through electrostatic interactions, concentrating and orienting the oligomers, facilitating the formation of higher molecular weight aggregates. This model raises the possibility that GAGs may play a protective role in human amyloid diseases by interacting with proteotoxic oligomers and promoting their association into less toxic amyloid fibrils.
机译：糖胺聚糖（GAGs）与人体内所有细胞外淀粉样沉积物有关，被发现可在体外加速各种淀粉样蛋白的聚集。然而，GAG促进淀粉样蛋白形成的精确分子机制仍然难以捉摸。在这里，我们表明，硫酸化的GAG，尤其是肝素，通过四级结构转化促进甲状腺素转运蛋白（TTR）的淀粉样蛋白生成。肝素上的硫酸根团簇及其聚合性质是加速TTR淀粉样蛋白生成的基本特征。肝素不影响TTR四聚体稳定性或TTR解离动力学，也不直接改变折叠的单体与折叠的单体平衡。取而代之的是，肝素加速了预先形成的TTR低聚物向较大聚集体的转化。在肝素的存在下，单体TTR消失得更快，这可能反映了以下事实：单体错折叠的淀粉样蛋白生成的单体-低聚物-TTR原纤维平衡都被联系在一起，这一假设得到了光散射数据的有力支持。在肝素存在下制备的TTR聚集体对胰蛋白酶和蛋白酶K的蛋白水解表现出较高的抵抗力，而对包含疏水簇的疏水侧链的暴露则较低，这表明肝素在淀粉样蛋白生成中具有积极作用。我们的数据表明，肝素通过基于支架的机制加速TTR聚集，其中包含GAG的硫酸根基团主要通过静电相互作用与TTR低聚物相互作用，使低聚物浓缩和定向，从而有助于形成更高分子量的聚集体。该模型通过与蛋白毒性低聚物相互作用并促进它们与毒性较小的淀粉样原纤维的缔合，增加了GAG在人淀粉样疾病中起保护作用的可能性。

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