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首页> 外文期刊>Journal of Molecular Biology >Synergistic Amyloid Switch Triggered by Early Heterotypic Oligomerization of Intrinsically Disordered α-Synuclein and Tau
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Synergistic Amyloid Switch Triggered by Early Heterotypic Oligomerization of Intrinsically Disordered α-Synuclein and Tau

机译：由本机α-突触核蛋白和TAU的早期异型寡聚化引发的协同淀粉样蛋白开关

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Amyloidogenic intrinsically disordered proteins, α-synuclein and tau are linked to Parkinson's disease and Alzheimer's disease, respectively. A body of evidence suggests that α-synuclein and tau, both present in the presynaptic nerve terminals, co-aggregate in many neurological ailments. The molecular mechanism of α-synuclein-tau hetero-assembly is poorly understood. Here we show that amyloid formation is synergistically facilitated by heterotypic association mediated by binding-induced misfolding of both α-synuclein and tau K18. We demonstrate that the intermolecular association is largely driven by the electrostatic interaction between the negatively charged C-terminal segment of α-synuclein and the positively charged tau K18 fragment. This heterotypic association results in rapid formation of oligomers that readily mature into hetero-fibrils with a much shorter lag phase compared to the individual proteins. These findings suggested that the critical intermolecular interaction between α-synuclein and tau can promote facile amyloid formation that can potentially lead to efficient sequestration of otherwise long-lived lethal oligomeric intermediates into innocuous fibrils. We next show that a well-known familial Parkinson's disease mutant (A30P) that is known to aggregate slowly via accumulation of highly toxic oligomeric species during the long lag phase converts into amyloid fibrils significantly faster in the presence of tau K18. The early intermolecular interaction profoundly accelerates the fibrillation rate of A30P α-synuclein and impels the disease mutant to behave similar to wild-type α-synuclein in the presence of tau. Our findings suggest a mechanistic underpinning of bypassing toxicity and suggest a general strategy by which detrimental amyloidogenic precursors are efficiently sequestered into more benign amyloid fibrils.
机译：淀粉样蛋白内部无序的蛋白质，α-突触核蛋白和TAU分别与帕金森病和阿尔茨海默病联系起来。证据表明，α-突触核蛋白和Tau，既存在于突触前神经末端，在许多神经疾病中共合。 α-突触核蛋白 - Tau杂组件的分子机制较差地理解。在这里，我们表明淀粉样蛋白形成由通过α-突触核蛋白和TAU K18的结合诱导的错误折叠介导的异质型相关协同促进。我们证明分子间关联在很大程度上被α-突触核蛋白的带负电荷的C末端区段与带正电荷的TAU K18片段之间的静电相互作用驱动。这种异型关联导致寡聚体的快速形成，其与各个蛋白质相比具有更短的滞后阶段的杂纤维。这些发现表明，α-突触核蛋白和Tau之间的临界分子间相互作用可以促进容易淀粉样蛋白形成，其可能导致诸如诸如长寿命的致死的寡聚体中间体的有效螯合成无害的原纤维。接下来，我们显示众所周知的家族式帕金森病突变体（A30P），该疾病突变体（A30P）通过在长滞后期间的高毒性寡聚物种期间缓慢聚集在Tau K18存在下显着更快地转化为淀粉样蛋白原纤维。早期的分子间相互作用深刻加速A30Pα-突触核蛋白的原纤化率，并促使疾病突变体表现得类似于TAU存在的野生型α-突触核蛋白。我们的研究结果表明了一种绕过毒性的机械效力，并提出了一种有害的淀粉样品前体被有效地螯合成更多的良性淀粉样蛋白原纤维的一般策略。

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