α-Synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis
α-Synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis
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DOI：
10.1038/embor.2010.66
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发表时间：
2010-07-01
期刊：
影响因子：
7.7
通讯作者：
Davletov, Bazbek
中科院分区：
文献类型：
--
作者：
Darios, Frederic;Ruiperez, Violeta;Davletov, Bazbek
α-突触核蛋白是参与帕金森病发病机制的突触调节蛋白。这种小胞质蛋白的确切功能仍在研究中。已经提出α-突触核蛋白调节参与囊泡融合的可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白。有趣的是，α-突触核蛋白在传统的蛋白质结合试验中不能与SNARE蛋白相互作用，因此表明了间接的作用模式。由于α-突触核蛋白和SNARE蛋白的结构和功能特性可以通过花生四烯酸（一种常见的脂质调节剂）进行修饰，我们详细分析了这种可能的三方联系。在这里，我们表明花生四烯酸刺激SNARE复合物的形成和胞吐的能力可以控制的α-突触核蛋白，在体外和体内。α-突触核蛋白螯合花生四烯酸，从而阻断SNARE的激活。我们的数据提供了对α-突触核蛋白在神经传递调制中的作用的机械见解。
alpha-Synuclein is a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease. The precise functions of this small cytosolic protein are still under investigation. alpha-Synuclein has been proposed to regulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicle fusion. Interestingly, alpha-synuclein fails to interact with SNARE proteins in conventional protein-binding assays, thus suggesting an indirect mode of action. As the structural and functional properties of both alpha-synuclein and the SNARE proteins can be modified by arachidonic acid, a common lipid regulator, we analysed this possible tripartite link in detail. Here, we show that the ability of arachidonic acid to stimulate SNARE complex formation and exocytosis can be controlled by alpha-synuclein, both in vitro and in vivo. alpha-Synuclein sequesters arachidonic acid and thereby blocks the activation of SNAREs. Our data provide mechanistic insights into the action of alpha-synuclein in the modulation of neurotransmission.