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Multiple roles of heparin in the aggregation of p25α

机译：肝素在p25α聚集中的多种作用

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The 219-residue protein p25α stimulates the fibrillation of α-synuclein (αSN) in vitro and colocalizes with it in several α-synucleinopathies. Although p25α does not fibrillate by itself under native conditions in vitro, αSN-free p25α aggregates have also been observed in vivo in, for example, multiple system atrophy. To investigate which environmental conditions might trigger this aggregation, we investigated the effect of polyanionic biomolecules on p25α aggregation. Heparin, polyglutamate, arachidonic acid micelles, and RNA all induce p25α aggregation. More detailed studies using heparin as template for aggregation reveal that a minimum of 10-14 heparin monosaccharide units per heparin polymer are required. Bona fide fibrils are only formed at intermediate heparin concentrations, possibly because an excess of heparin binding sites blocks the inter-p25α contacts required for amyloid formation. Other polyanions also show an optimum for amyloid formation. Aggregation involves only modest structural changes according to both spectroscopic and proteolytic experiments. The aggregates do not seed aggregation of heparin-free p25α, suggesting that heparin is required in stoichiometric amounts to form organized structures. We are able to reproduce these observations in a model involving two levels of binding of p25α to heparin. We conclude that the modest structural changes that p25α undergoes can promote weak intermolecular contacts and that polyanions such as heparin play a central role in stabilizing these aggregates but in multiple ways, leading to different types of aggregates. This highlights the role of non-protein components in promoting protein aggregation in vivo.
机译：219个残基蛋白p25α在体外刺激α-突触核蛋白（αSN）的原纤维化，并在几种α-突触核病中与其共定位。尽管在体外自然条件下p25α本身不会原纤化，但在体内例如多系统萎缩中也观察到了无αSN的p25α聚集体。为了研究哪些环境条件可能触发这种聚集，我们研究了聚阴离子生物分子对p25α聚集的影响。肝素，聚谷氨酸，花生四烯酸胶束和RNA均可诱导p25α聚集。使用肝素作为聚集模板的更详细的研究表明，每个肝素聚合物至少需要10-14个肝素单糖单元。真正的原纤维仅在中等肝素浓度下形成，可能是因为过量的肝素结合位点阻断了淀粉样蛋白形成所需的p25α间接触。其他聚阴离子也显示出淀粉样蛋白形成的最佳状态。根据光谱和蛋白水解实验，聚集仅涉及适度的结构变化。聚集体不包含无肝素的p25α的种子聚集体，这表明以化学计量的量需要肝素才能形成有组织的结构。我们能够在涉及p25α与肝素两个结合水平的模型中重现这些观察结果。我们得出的结论是，p25α经历的适度结构变化可以促进弱分子间接触，聚阴离子（例如肝素）在稳定这些聚集体中起着核心作用，但是以多种方式导致了不同类型的聚集体。这突出了非蛋白质成分在体内促进蛋白质聚集的作用。

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