Pallbo Jon, Imai Masayuki, Gentile Luigi, Takata Shin-Ichi, Olsson Ulf, Sparr Emma
Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden.
Department of Physics, Graduate School of Science, Tohoku University, Sendai, Japan.
Front Physiol. 2020 Dec 18;11:592117. doi: 10.3389/fphys.2020.592117. eCollection 2020.
Amyloids are implicated in many diseases, and disruption of lipid membrane structures is considered as one possible mechanism of pathology. In this paper we investigate interactions between an aggregating peptide and phospholipid membranes, focusing on the nanometer-scale structures of the aggregates formed, as well as on the effect on the aggregation process. As a model system, we use the small amyloid-forming peptide named NACore, which is a fragment of the central region of the protein α-synuclein that is associated with Parkinson's disease. We find that phospholipid vesicles readily associate with the amyloid fibril network in the form of highly distorted and trapped vesicles that also may wet the surface of the fibrils. This effect is most pronounced for model lipid systems containing only zwitterionic lipids. Fibrillation is found to be retarded by the presence of the vesicles. At the resolution of our measurements, which are based mainly on cryogenic transmission electron microscopy (cryo-TEM), X-ray scattering, and circular dichroism (CD) spectroscopy, we find that the resulting aggregates can be well fitted as linear combinations of peptide fibrils and phospholipid bilayers. There are no detectable effects on the cross-β packing of the peptide molecules in the fibrils, or on the thickness of the phospholipid bilayers. This suggests that while the peptide fibrils and lipid bilayers readily co-assemble on large length-scales, most of them still retain their separate structural identities on molecular length-scales. Comparison between this relatively simple model system and other amyloid systems might help distinguish aspects of amyloid-lipid interactions that are generic from aspects that are more protein specific. Finally, we briefly consider possible implications of the obtained results for amyloid toxicity.
淀粉样蛋白与多种疾病有关，脂质膜结构的破坏被认为是一种可能的病理机制。在本文中，我们研究了聚集肽与磷脂膜之间的相互作用，重点关注所形成聚集体的纳米级结构以及对聚集过程的影响。作为一个模型系统，我们使用名为NACore的小淀粉样形成肽，它是与帕金森病相关的蛋白质α-突触核蛋白中心区域的一个片段。我们发现磷脂囊泡很容易以高度扭曲和被困的囊泡形式与淀粉样纤维网络结合，这些囊泡也可能会浸湿纤维表面。这种效应在仅含有两性离子脂质的模型脂质系统中最为明显。发现囊泡的存在会延迟纤维化。在我们主要基于低温透射电子显微镜（cryo-TEM）、X射线散射和圆二色性（CD）光谱的测量分辨率下，我们发现所形成的聚集体可以很好地拟合为肽纤维和磷脂双层的线性组合。对纤维中肽分子的交叉β堆积或磷脂双层的厚度没有可检测到的影响。这表明，虽然肽纤维和脂质双层在大长度尺度上很容易共同组装，但它们中的大多数在分子长度尺度上仍然保留其各自的结构特征。将这个相对简单的模型系统与其他淀粉样系统进行比较，可能有助于区分淀粉样蛋白-脂质相互作用中普遍存在的方面和更具蛋白质特异性的方面。最后，我们简要考虑了所得结果对淀粉样蛋白毒性的可能影响。
