Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes.
Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes.
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淀粉样细丝形成的分子机制：α-突触核蛋白在脂膜上的节段性折叠。
DOI：
10.1126/sciadv.abg2174
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发表时间：
2021-05
期刊：
影响因子：
13.6
通讯作者：
Griesinger C
中科院分区：
文献类型：
--
作者：
Antonschmidt L;Dervişoğlu R;Sant V;Tekwani Movellan K;Mey I;Riedel D;Steinem C;Becker S;Andreas LB;Griesinger C
帕金森病相关的α-突触核蛋白在脂质体上聚集的中间体的结构通过NMR表征。疾病相关α-突触核蛋白原纤维结构生物学的最新进展揭示了多种结构，但对原纤维聚集体形成过程知之甚少。在聚集过程中形成的中间物种的表征是至关重要的;然而，这已被证明是非常具有挑战性的，因为它们的短暂性，异质性和低种群。在这里，我们研究了α-突触核蛋白结合到带负电荷的磷脂小单层囊泡的聚集。通过结合动力学和结构研究，我们确定了聚集过程中的关键时间点，使有针对性的分离prefibrillar和早期fibrillar中间体。通过使用固态核磁共振，我们显示了α-突触核蛋白纤维丝结构特征的逐渐建立，揭示了节段性折叠过程。我们在α-突触核蛋白聚集体中鉴定了不同的膜结合结构域，并且结合的数据用于呈现α-突触核蛋白在脂质膜上折叠的综合机制。
Aggregation intermediates of Parkinson’s disease–related α-synuclein on liposomes are structurally characterized by NMR. Recent advances in the structural biology of disease-relevant α-synuclein fibrils have revealed a variety of structures, yet little is known about the process of fibril aggregate formation. Characterization of intermediate species that form during aggregation is crucial; however, this has proven very challenging because of their transient nature, heterogeneity, and low population. Here, we investigate the aggregation of α-synuclein bound to negatively charged phospholipid small unilamellar vesicles. Through a combination of kinetic and structural studies, we identify key time points in the aggregation process that enable targeted isolation of prefibrillar and early fibrillar intermediates. By using solid-state nuclear magnetic resonance, we show the gradual buildup of structural features in an α-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane-binding domains in α-synuclein aggregates, and the combined data are used to present a comprehensive mechanism of the folding of α-synuclein on lipid membranes.
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影响因子：
16.6
作者：
Fusco, Giuliana;Pape, Tillmann;Stephens, Amberley D.;Mahou, Pierre;Costa, Ana Rita;Kaminski, Clemens F.;Schierle, Gabriele S. Kaminski;Vendruscolo, Michele;Veglia, Gianluigi;Dobson, Christopher M.;De Simone, Alfonso
通讯作者：
De Simone, Alfonso
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：
0.9
作者：
Gath, Julia;Bousset, Luc;Boeckmann, Anja
通讯作者：
Boeckmann, Anja
影响因子：
14.5
作者：
GIBB, WRG;ESIRI, MM;LEES, AJ
通讯作者：
LEES, AJ
影响因子：
3.2
作者：
Drescher, Malte;Godschalk, Frans;Huber, Martina
通讯作者：
Huber, Martina