C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.
C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.
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DOI：
10.1038/s41467-018-03111-4
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发表时间：
2018-02-19
影响因子：
16.6
通讯作者：
Schierle GSK
中科院分区：
文献类型：
--
作者：
Lautenschläger J;Stephens AD;Fusco G;Ströhl F;Curry N;Zacharopoulou M;Michel CH;Laine R;Nespovitaya N;Fantham M;Pinotsi D;Zago W;Fraser P;Tandon A;St George-Hyslop P;Rees E;Phillips JJ;De Simone A;Kaminski CF;Schierle GSK
已知α -突触核蛋白通过其N端与小单层囊泡（suv）结合，在膜相互作用下形成两亲性α -螺旋。在这里，我们发现钙结合到α -突触核蛋白的C端，从而增加其脂质结合能力。利用CEST-NMR，我们发现α -突触核蛋白通过两个区域与孤立的突触囊泡相互作用，一个是在suv研究中已知的N端，另一个是通过它的C端，这是由钙结合调节的。确实，突触体上的dSTORM表明，钙介导α -突触核蛋白在突触前末端的定位，钙或α -突触核蛋白的不平衡会导致突触囊泡聚集，这在体内和体外都可以看到。本研究提供了α -突触核蛋白与突触囊泡结合的新观点，这也可能影响我们对突触核蛋白病的理解。突触核蛋白与帕金森病的神经元功能障碍有关。这项研究表明-突触核蛋白以钙依赖的方式与神经元突触囊泡相互作用，这种相互作用对突触囊泡聚集很重要。
Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies. Alpha-synuclein is associated with neuronal dysfunction in Parkinson’s disease. This study shows that alpha-synuclein interacts with neuronal synaptic vesicles in a calcium-dependent fashion, and this interaction is important for synaptic vesicle clustering.
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影响因子：
16.6
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
通讯作者：
De Simone, Alfonso
影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
14.8
作者：
Dunkley, Peter R.;Jarvie, Paula E.;Robinson, Phillip J.
通讯作者：
Robinson, Phillip J.
影响因子：
3.3
作者：
Huang, Hao;Milojevic, Julijana;Melacini, Giuseppe
通讯作者：
Melacini, Giuseppe
DOI：
10.1111/j.1749-6632.1992.tb24523.x
发表时间：
1992-05-11
影响因子：
5.2
作者：
GERMAN, DC;MANAYE, KF;BROOKS, BA
通讯作者：
BROOKS, BA