Biophysical properties of the synucleins and their propensities to fibrillate -: Inhibition of α-synuclein assembly by β- and γ-synucleins
Biophysical properties of the synucleins and their propensities to fibrillate -: Inhibition of α-synuclein assembly by β- and γ-synucleins
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DOI：
10.1074/jbc.m109541200
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发表时间：
2002-04-05
影响因子：
4.8
通讯作者：
Fink, AL
中科院分区：
文献类型：
--
作者：
Uversky, VN;Li, J;Fink, AL
帕金森病的病理特征是黑质和其他几个脑区的多巴胺能神经元中存在细胞内包涵体、路易体和路易神经突。菲拉。 mentous a-synuclein 是这些沉积物的主要成分，其聚集被认为在帕金森病和其他几种神经退行性疾病中发挥着重要作用。两种同源蛋白，β-突触核蛋白和γ-突触核蛋白，在大脑中也含量丰富。突触核蛋白是天然未折叠的蛋白质。 β-突触核蛋白与其同源物相比缺乏 11 个中心疏水残基，表现出随机卷曲的特性，而 α-和 γ-突触核蛋白则稍微更加紧凑和结构化。与其同系物不同，γ-突触核蛋白在相对较低的浓度下形成可溶性寡聚物，这似乎是一种非纤维化途径物种。在这里，我们表明，尽管β-突触核蛋白和γ-突触核蛋白具有与α-突触核蛋白相似的生物物理特性，但它们抑制α-突触核蛋白原纤维的形成。在 4:1 摩尔过量的 β- 和 γ-突触核蛋白中观察到对 α-突触核蛋白纤维颤动的完全抑制。未检测到β-突触核蛋白显着掺入原纤维中。缺乏由 β-突触核蛋白形成的原纤维最容易解释为蛋白质中部区域不存在一段疏水性残基。提出了抑制模型。
The pathological hallmark of Parkinson's disease is the presence of intracellular inclusions, Lewy bodies, and Lewy neurites, in the dopaminergic neurons of the substantia nigra and several other brain regions. Fila. mentous a-synuclein is the major component of these deposits and its aggregation is believed to play an important role in Parkinson's disease and several other neurodegenerative diseases. Two homologous proteins, beta- and gamma-synucleins, are also abundant in the brain. The synucleins are natively unfolded proteins. beta-Synuclein, which lacks 11 central hydrophobic residues compared with its homologs, exhibited the properties of a random coil, whereas alpha- and gamma-synucleins were slightly more compact and structured. gamma-Synuclein, unlike its homologs, formed a soluble oligomer at relatively low concentrations, which appears to be an off-fibrillation pathway species. Here we show that, although they have similar biophysical properties to alpha-synuclein, beta- And gamma-synucleins inhibit a-synuclein fibril formation. Complete inhibition of a-synuclein fibrillation was observed at 4:1 molar excess of beta- and gamma-synucleins. No significant incorporation of beta-synuclein into the fibrils was detected. The lack of fibrils formed by beta-synuclein is most readily explained by the absence of a stretch of hydrophobic residues from the middle region of the protein. A model for the inhibition is proposed.