Membrane lipid co-aggregation with α-synuclein fibrils.
Membrane lipid co-aggregation with α-synuclein fibrils.
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DOI：
10.1371/journal.pone.0077235
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sparr E
中科院分区：
文献类型：
--
作者：
Hellstrand E;Nowacka A;Topgaard D;Linse S;Sparr E
几种人类疾病的淀粉样沉积已被发现含有膜脂。脂肪和淀粉样蛋白在淀粉样蛋白聚集体中的共同聚集，以及相关的从细胞膜中提取脂类，可以影响细胞膜和形成的淀粉样蛋白沉积的结构和功能。因此，共聚集可以对淀粉样蛋白形成的病理后果产生重要的影响。然而，人们对共聚集背后的机制和形成的聚集体中的分子结构知之甚少。为了解决这个问题，我们通过将磷脂模型膜与帕金森病相关蛋白α-突触核蛋白以单体形式孵育来研究体外共聚集。聚集后，我们发现磷脂从阴离子模型膜自发摄取到淀粉样纤维中。磷脂定量、极化转移固体核磁共振和低温电子显微镜共同揭示了磷脂和α-突触核蛋白以可饱和的方式共聚集，并且强烈依赖于脂质组成。在低脂蛋白比时，磷脂与纤维结构密切相关，这从磷脂流动性降低和纤维束的形态变化中可见一斑。当脂肪与蛋白质的比例较高时，更多的小泡会沿着纤维吸附。虽然脂类和淀粉样蛋白之间的相互作用通常是从不同蛋白质物种吸附和扰动脂膜的角度来讨论的，但目前的工作揭示了在脂类存在的情况下淀粉样蛋白的形成是一个共同聚集的过程。这种相互作用导致脂蛋白共聚体的形成，与脂类或蛋白质单独形成的集合体相比，它们具有截然不同的结构、动力学和形态。
Amyloid deposits from several human diseases have been found to contain membrane lipids. Co-aggregation of lipids and amyloid proteins in amyloid aggregates, and the related extraction of lipids from cellular membranes, can influence structure and function in both the membrane and the formed amyloid deposit. Co-aggregation can therefore have important implications for the pathological consequences of amyloid formation. Still, very little is known about the mechanism behind co-aggregation and molecular structure in the formed aggregates. To address this, we study in vitro co-aggregation by incubating phospholipid model membranes with the Parkinson’s disease-associated protein, α-synuclein, in monomeric form. After aggregation, we find spontaneous uptake of phospholipids from anionic model membranes into the amyloid fibrils. Phospholipid quantification, polarization transfer solid-state NMR and cryo-TEM together reveal co-aggregation of phospholipids and α-synuclein in a saturable manner with a strong dependence on lipid composition. At low lipid to protein ratios, there is a close association of phospholipids to the fibril structure, which is apparent from reduced phospholipid mobility and morphological changes in fibril bundling. At higher lipid to protein ratios, additional vesicles adsorb along the fibrils. While interactions between lipids and amyloid-protein are generally discussed within the perspective of different protein species adsorbing to and perturbing the lipid membrane, the current work reveals amyloid formation in the presence of lipids as a co-aggregation process. The interaction leads to the formation of lipid-protein co-aggregates with distinct structure, dynamics and morphology compared to assemblies formed by either lipid or protein alone.
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影响因子：
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