The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.
The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.
复制标题
α-突触核蛋白的C末端可以预防骨料复制，但对于低聚至关重要。
DOI：
10.1038/s42003-022-03059-8
复制
发表时间：
2022-02-10
影响因子：
5.9
通讯作者：
Otzen DE
中科院分区：
文献类型：
--
作者：
Farzadfard A;Pedersen JN;Meisl G;Somavarapu AK;Alam P;Goksøyr L;Nielsen MA;Sander AF;Knowles TPJ;Pedersen JS;Otzen DE
α-突触核蛋白（α-synuclein，αSN）由140个氨基酸残基组成，其聚集是帕金森病（Parkinson's disease，PD）发病的关键因素。虽然αSN的强阴离子C末端结构域（CTD）不构成淀粉样蛋白核心区的一部分或影响膜结合能力，但CTD中电荷的截短或减少通过未知机制促进纤维化。在这里，我们研究逐步截断CTD和确定残基121周围的阈值区域，比这短的结构显着增加他们的纤颤倾向。值得注意的是，即使只有10%的截短变体与全长蛋白质混合，这些效果也会持续存在。纤维性颤动的增加可以通过自我复制的大幅增加来解释，最有可能是通过碎片化。自相矛盾的是，截短还抑制了有毒低聚物的形成，而通过化学修饰形成的低聚物显示出降低的膜亲和力和细胞毒性。这些显著的变化与CTD中负静电势的损失相关，并突出了静电安全防护的双刃剑。Farzadfard等人对aSN的一系列C末端截短进行了全面分析，将高C末端电荷对降低纤颤率的重要性联系起来。截短的aSN降低了形成寡聚体、破坏合成囊泡和细胞毒性的能力，有助于理解促进/抑制聚集的aSN的分子内相互作用。
Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson’s disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency. Remarkably, these effects persist even when as little as 10% of the truncated variant is mixed with the full-length protein. Increased fibrillation can be explained by a substantial increase in self-replication, most likely via fragmentation. Paradoxically, truncation also suppresses toxic oligomer formation, and oligomers that can be formed by chemical modification show reduced membrane affinity and cytotoxicity. These remarkable changes correlate to the loss of negative electrostatic potential in the CTD and highlight a double-edged electrostatic safety guard. Farzadfard et al. present a comprehensive analysis of a range of C-terminal truncations of aSN, linking the importance of high C-terminus charge for decreased fibrillation rates. The ability to formation oligomers, to disrupt synthetic vesicles and cell toxicity was reduced with truncated aSN, aiding in understanding of the intramolecular interactions of aSN which promote/inhibit aggregation.
登录
查看更多内容
影响因子：
16.6
作者：
Lautenschläger J;Stephens AD;Fusco G;Ströhl F;Curry N;Zacharopoulou M;Michel CH;Laine R;Nespovitaya N;Fantham M;Pinotsi D;Zago W;Fraser P;Tandon A;St George-Hyslop P;Rees E;Phillips JJ;De Simone A;Kaminski CF;Schierle GSK
通讯作者：
Schierle GSK
影响因子：
7.4
作者：
Almandoz-Gil, Leire;Welander, Hedvig;Bergstrom, Joakim
通讯作者：
Bergstrom, Joakim
影响因子：
4.8
作者：
Liu, CW;Giasson, BI;Thomas, PJ
通讯作者：
Thomas, PJ
DOI：
10.1111/j.1460-9568.2010.07266.x
发表时间：
2010-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Feng LR;Federoff HJ;Vicini S;Maguire-Zeiss KA
通讯作者：
Maguire-Zeiss KA
影响因子：
13.6
作者：
Antonschmidt L;Dervişoğlu R;Sant V;Tekwani Movellan K;Mey I;Riedel D;Steinem C;Becker S;Andreas LB;Griesinger C
通讯作者：
Griesinger C