Sulfated glycosaminoglycans accelerate transthyretin amyloidogenesis by quaternary structural conversion.
Sulfated glycosaminoglycans accelerate transthyretin amyloidogenesis by quaternary structural conversion.
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DOI：
10.1021/bi101822y
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发表时间：
2011-02-15
期刊：
影响因子：
2.9
通讯作者：
Kelly JW
中科院分区：
文献类型：
--
作者：
Bourgault S;Solomon JP;Reixach N;Kelly JW
已知糖胺聚糖（GAGs）与人类所有细胞外淀粉样蛋白沉积有关，可在体外加速各种淀粉样蛋白的聚集。然而，GAGs加速淀粉样蛋白形成的确切分子机制尚不清楚。在此，我们发现硫酸酸化的GAGs，特别是肝素，通过四级结构转化加速甲状腺转蛋白（TTR）淀粉样蛋白的形成。硫酸基团在肝素上的聚集及其聚合性质是加速TTR淀粉样蛋白形成的重要特征。肝素不影响TTR四聚体的稳定性或TTR解离动力学，也不直接改变折叠单体-错误折叠单体的平衡。相反，肝素加速了预形成的TTR低聚物转化为更大的聚集体。在肝素存在的情况下，单体TTR更快地消失可能反映了这样一个事实，即单体-错误折叠的淀粉样蛋白单体-低聚物- TTR纤维平衡都是相互关联的——光散射数据有力地支持了这一假设。在肝素存在下制备的TTR聚集体对胰蛋白酶和蛋白酶K蛋白水解具有更高的抗性，并且包含疏水簇的疏水侧链暴露较少，表明其在淀粉样蛋白形成中起积极作用。我们的数据表明，肝素通过一种基于支架的机制加速TTR的聚集，其中包含GAGs的硫酸盐基团主要通过静电相互作用与TTR低聚物相互作用，使低聚物集中和定向，促进高分子量聚集体的形成。该模型提出了一种可能性，即GAGs可能通过与蛋白毒性低聚物相互作用并促进它们结合成毒性较小的淀粉样蛋白原纤维，从而在人类淀粉样蛋白疾病中发挥保护作用。
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 presence of heparin showed a higher resistance to trypsin and proteinase K proteolysis and a lower exposure of hydrophobic side chains comprising hydrophobic clusters, suggesting an active role 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.
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