Structural basis of synaptic vesicle assembly promoted by α-synuclein.
Structural basis of synaptic vesicle assembly promoted by α-synuclein.
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DOI：
10.1038/ncomms12563
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发表时间：
2016-09-19
影响因子：
16.6
通讯作者：
De Simone, Alfonso
中科院分区：
文献类型：
--
作者：
Fusco, Giuliana;Pape, Tillmann;Stephens, Amberley D.;Mahou, Pierre;Costa, Ana Rita;Kaminski, Clemens F.;Schierle, Gabriele S. Kaminski;Vendruscolo, Michele;Veglia, Gianluigi;Dobson, Christopher M.;De Simone, Alfonso
α-突触核蛋白 (αS) 是一种本质上无序的蛋白质，其纤维状聚集体是帕金森病路易体的主要成分。尽管αS的具体功能仍不清楚，但人们普遍认为它在调节神经递质释放过程中发挥着关键作用，这与介导突触小泡相互作用和组装有关。在这里，我们报告了对野生型αS和与家族性帕金森病相关的两种突变变体的分析，以描述使αS能够诱导突触小泡聚集的分子机制的结构基础。我们通过合理设计和实验测试αS的进一步突变变体，为这种“双锚”机制提供支持，该突变变体被设计为促进突触小泡之间更强的相互作用。我们的结果描述了介导突触小泡聚集的αS活性构象的性质，并表明它们在功能和病理背景中的相关性。 α-突触核蛋白是一种与帕金森病相关的蛋白质，参与突触小泡的相互作用和组装。在这里，作者使用核磁共振波谱和超分辨率显微镜揭示了 α-突触核蛋白介导的突触小泡聚类的性质和分子机制。
α-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson's disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor' mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts. α-synuclein, a protein associated to Parkinson's disease, is involved in synaptic vesicle interaction and assembly. Here, the authors use NMR spectroscopy and super-resolution microscopy to unveil the nature and molecular mechanism of α-synuclein-mediated synaptic vesicle clustering.
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