Structural basis for the dissociation of α-synuclein fibrils triggered by pressure perturbation of the hydrophobic core.
Structural basis for the dissociation of α-synuclein fibrils triggered by pressure perturbation of the hydrophobic core.
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DOI：
10.1038/srep37990
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发表时间：
2016-11-30
影响因子：
4.6
通讯作者：
Silva JL
中科院分区：
文献类型：
--
作者：
de Oliveira GA;Marques MA;Cruzeiro-Silva C;Cordeiro Y;Schuabb C;Moraes AH;Winter R;Oschkinat H;Foguel D;Freitas MS;Silva JL
帕金森病（Parkinson's disease，PD）是一种神经系统疾病，α-synuclein（α-syn）蛋白质以聚集的形式存在，我们利用高静水压（HHP）结合核磁共振（NMR）技术研究了α-syn原纤维的解离过程，并对其结构和动力学性质进行了评价。通过HHP NMR光谱鉴定了构成Greek-key疏水核心的非淀粉样蛋白-β组分（NAC）和蛋白质的酸性C-末端区域中的不同动力学性质。此外，固态NMR揭示了HHP干扰的原纤维核心的细微差异，为这些物种如何促进种子α-syn聚集提供了线索。这些发现显示了压力如何填充迄今未被检测到的α-syn物种，并且它们通过以前使用其他方法未观察到的途径为原纤维解离绘制了路线图。压力通过将水向内推而扰乱原纤维的倾向于空腔的疏水核心，从而诱导解离成单体。我们的研究提供了疏水相互作用和水排斥腔的形成如何共同有助于原纤维的组装和稳定的分子细节。了解压力扰动揭示的致病原纤维形成背后的分子力将有助于开发针对帕金森病的新疗法。
Parkinson’s disease is a neurological disease in which aggregated forms of the α-synuclein (α-syn) protein are found. We used high hydrostatic pressure (HHP) coupled with NMR spectroscopy to study the dissociation of α-syn fibril into monomers and evaluate their structural and dynamic properties. Different dynamic properties in the non-amyloid-β component (NAC), which constitutes the Greek-key hydrophobic core, and in the acidic C-terminal region of the protein were identified by HHP NMR spectroscopy. In addition, solid-state NMR revealed subtle differences in the HHP-disturbed fibril core, providing clues to how these species contribute to seeding α-syn aggregation. These findings show how pressure can populate so far undetected α-syn species, and they lay out a roadmap for fibril dissociation via pathways not previously observed using other approaches. Pressure perturbs the cavity-prone hydrophobic core of the fibrils by pushing water inward, thereby inducing the dissociation into monomers. Our study offers the molecular details of how hydrophobic interaction and the formation of water-excluded cavities jointly contribute to the assembly and stabilization of the fibrils. Understanding the molecular forces behind the formation of pathogenic fibrils uncovered by pressure perturbation will aid in the development of new therapeutics against Parkinson’s disease.
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影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
DOI：
10.1016/s1474-4422(15)00006-x
发表时间：
2015-08
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Dehay B;Bourdenx M;Gorry P;Przedborski S;Vila M;Hunot S;Singleton A;Olanow CW;Merchant KM;Bezard E;Petsko GA;Meissner WG
通讯作者：
Meissner WG
影响因子：
3.4
作者：
Bartels, Tim;Ahlstrom, Logan S.;Beyer, Klaus
通讯作者：
Beyer, Klaus
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
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