Phosphatidylcholine and Phosphatidylserine Uniquely Modify the Secondary Structure of α-Synuclein Oligomers Formed in Their Presence at the Early Stages of Protein Aggregation.
Phosphatidylcholine and Phosphatidylserine Uniquely Modify the Secondary Structure of α-Synuclein Oligomers Formed in Their Presence at the Early Stages of Protein Aggregation.
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DOI：
10.1021/acschemneuro.2c00355
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发表时间：
2022-08-17
影响因子：
5
通讯作者：
Kurouski, Dmitry
中科院分区：
文献类型：
--
作者：
Dou, Tianyi;Kurouski, Dmitry
关键词：
α-突触核蛋白 (α-Syn) 的突然聚集会导致形成剧毒的蛋白质寡聚物。这些聚集物是中脑、下丘脑和丘脑中多巴胺能神经元不可逆变性（一种称为帕金森病的病理学）发生的根本分子原因。低聚物的瞬态性质及其结构和形态异质性限制了冷冻电子显微镜和固态核磁共振（结构生物学的经典工具）用于阐明其二级结构的使用。尽管存在这种限制，大量实验证据表明磷脂可以独特地改变低聚物的结构和毒性。在这项研究中，我们利用创新的纳米红外成像技术，也称为原子力显微镜红外 (AFM-IR) 光谱，来检查在磷脂酰胆碱 (α-Syn:PC) 和磷脂酰丝氨酸 (α-Syn:PS) 存在下生长的单个 α-Syn 低聚物的结构。我们测定了蛋白质聚集开始后第 2 天 (D2)、第 8 天 (D8) 和第 15 天 (D15) 形成的 α-Syn:PC 和 α-Syn:PS 二级结构中平行和反平行 β-折叠的量，以及 α-螺旋和无序蛋白质的量。我们发现从 D2 到 D15，α-Syn:PC 和 α-Syn:PS 中平行 β-折叠的数量逐渐减少，同时 α-螺旋和无序蛋白质二级结构增加。我们推断这是由于寡聚物结构中存在脂质，在寡聚物与单体 α-Syn 相互作用时，脂质阻止了平行 β-折叠的扩展。
Abrupt aggregation of α-synuclein (α-Syn) leads to a formation of highly toxic protein oligomers. These aggregates are the underlying molecular cause of an onset of the irreversible degeneration of dopaminergic neurons in midbrain, hypothalamus, and thalamus, a pathology known as Parkinson’s disease. The transient nature of oligomers, as well as their structural and morphological heterogeneity, limits the use of cryo-electron microscopy and solid-state NMR, classical tools of structural biology, for elucidation of their secondary structure. Despite this limitation, numerous pieces of experimental evidence suggest that phospholipids can uniquely alter the structure and toxicity of oligomers. In this study, we utilize an innovative nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to examine the structure of individual α-Syn oligomers grown in the presence of phosphatidylcholine (α-Syn:PC) and phosphatidylserine (α-Syn:PS). We determined the amount of the parallel and the antiparallel β-sheets, as well as the amount the α-helix and the unordered protein, in the secondary structure of α-Syn:PC and α-Syn:PS formed at day 2 (D2), 8 (D8), and 15 (D15) after initiation of protein aggregation. We found a gradual decrease in the amount of the parallel β-sheet in both α-Syn:PC and α-Syn:PS from D2 to D15 together with an increase in the α-helix and the unordered protein secondary structure. We infer that this is due to the presence of lipids in the structure of oligomers that prevent an expansion of the parallel β-sheet upon interaction of the oligomers with monomeric α-Syn.
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影响因子：
2.9
作者：
Bodner, Christina R.;Maltsev, Alexander S.;Dobson, Christopher M.;Bax, Ad
通讯作者：
Bax, Ad
DOI：
10.1073/pnas.1421204112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Chen, Serene W.;Drakulic, Srdja;Cremades, Nunilo
通讯作者：
Cremades, Nunilo
影响因子：
3.4
作者：
Kurouski, Dmitry;Deckert-Gaudig, Tanja;Lednev, Igor K.
通讯作者：
Lednev, Igor K.
NMR观察到的蛋氨酸氧化速率探测的α-突触核蛋白和膜之间的位点特异性相互作用。
影响因子：
15
作者：
Maltsev, Alexander S.;Chen, Jue;Levine, Rodney L.;Bax, Ad
通讯作者：
Bax, Ad
影响因子：
3.4
作者：
Pfefferkorn, Candace M.;Jiang, Zhiping;Lee, Jennifer C.
通讯作者：
Lee, Jennifer C.