Bloch Daniel Nir, Miller Yifat
Department of Chemistry and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
ACS Omega. 2017 Jul 31;2(7):3363-3370. doi: 10.1021/acsomega.7b00459. Epub 2017 Jul 10.
Parkinson's disease is characterized by the self-assembly of α-synuclein (AS), in which its aggregates accumulate in the substantia nigra. The molecular mechanisms of the self-assembly of AS are challenging because AS is a relatively large intrinsically disordered protein, consisting of 140 residues. It is known that the N-termini of AS contribute to the toxicity of the proteins; therefore, it is important to investigate the self-assembly structure of the N-termini on AS as well. There have been extensive efforts to investigate the structural fibrils of AS(1-140), which have shown that the N-termini are disordered and do not participate in the fibrillary structure. This study illustrates for the first time that the N-termini of AS play a crucial role in the self-assembly of AS. This study reveals a new structure of AS(1-140) fibrils, in which the N-termini are essential parts of the cross-β structure of the fibrillary structure. This study suggests that there are polymorphic states of the self-assembled AS(1-140). While the polymorphic states of the N-termini do not participate in the fibrillary structure and fluctuate, our predicted new fibrillary structure of the N-termini not only participates in the fibrillary structure but also stabilizes the fibrillary structure.
帕金森病的特征是α-突触核蛋白（AS）的自组装，其聚集体在黑质中积累。AS自组装的分子机制具有挑战性，因为AS是一种相对较大的内在无序蛋白，由140个氨基酸残基组成。已知AS的N端对蛋白质的毒性有影响；因此，研究AS N端的自组装结构也很重要。人们已经广泛努力研究AS（1-140）的结构纤维，结果表明N端是无序的，不参与纤维结构。本研究首次表明，AS的N端在AS的自组装中起关键作用。本研究揭示了AS（1-140）纤维的一种新结构，其中N端是纤维结构交叉β结构的重要组成部分。本研究表明，自组装的AS（1-140）存在多态状态。虽然N端的多态状态不参与纤维结构且会波动，但我们预测的N端新纤维结构不仅参与纤维结构，还能稳定纤维结构。
