Biophysics of α-synuclein induced membrane remodelling.
Biophysics of α-synuclein induced membrane remodelling.
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DOI：
10.1039/c4cp05883f
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发表时间：
2015-06-28
期刊：
影响因子：
--
通讯作者：
Baumgart T
中科院分区：
文献类型：
--
作者：
Shi Z;Sachs JN;Rhoades E;Baumgart T
α-突触核蛋白是一种本质上无序的蛋白质，其聚集是帕金森病的标志。在神经元中，α-突触核蛋白被认为通过与脂质双层或其他蛋白质的相互作用，在介导突触小泡的内吞作用和胞吐作用中发挥重要作用。膜结合后，α-突触核蛋白的 N 末端形成螺旋结构并插入外膜小叶的疏水区域。然而，α-突触核蛋白引起的膜结构变化仍不清楚。在这里，我们报告了 α-突触核蛋白单体的结合引起的膜面积的显着扩张。该测量是通过观察 α-突触核蛋白与移液器吸取的巨型囊泡结合期间膜面积的增加来完成的。膜面积扩张的程度与膜上 α-突触核蛋白的密度线性相关，揭示了每个 α-突触核蛋白分子的结合诱导的恒定面积增加。发现每个突触核蛋白的面积扩张表现出对脂质成分的强烈依赖性，但与膜张力和囊泡大小无关。膜的破裂或管状化发生在膜膨胀过程之后。然而，与 BAR 结构域蛋白相反，显然无法识别 α-突触核蛋白的明显管状转变密度，这表明存在更复杂的膜曲率生成机制。考虑到 α-突触核蛋白的膜结合自由能和脂质双层的生物物理特性，我们得出结论：α-突触核蛋白的膜扩张导致双层变薄。这些膜变薄和管状效应可能是 α-突触核蛋白在介导细胞运输过程（例如胞吐作用和胞吐作用）中发挥作用的基础。
α-synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson’s disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of α-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of α-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of α-synuclein on the membrane, revealing a constant area increase induced by the binding per α-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for α-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of α-synuclein’s membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by α-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie α-synuclein’s role in mediating cell trafficking processes such as endo- and exocytosis.
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