Garten Matthias, Prévost Coline, Cadart Clotilde, Gautier Romain, Bousset Luc, Melki Ronald, Bassereau Patricia, Vanni Stefano
Institut Curie, Centre de Recherche, Paris, France.
Phys Chem Chem Phys. 2015 Jun 28;17(24):15589-97. doi: 10.1039/c5cp00244c. Epub 2015 Mar 31.
Alpha-synuclein (AS) is a synaptic protein that is directly involved in Parkinson's disease due to its tendency to form protein aggregates. Since AS aggregation can be dependent on the interactions between the protein and the cell plasma membrane, elucidating the membrane binding properties of AS is of crucial importance to establish the molecular basis of AS aggregation into toxic fibrils. Using a combination of in vitro reconstitution experiments based on Giant Unilamellar Vesicles (GUVs), confocal microscopy and all-atom molecular dynamics simulations, we have investigated the membrane binding properties of AS, with a focus on the relative contribution of hydrophobic versus electrostatic interactions. In contrast with previous observations, we did not observe any binding of AS to membranes containing the ganglioside GM1, even at relatively high GM1 content. AS, on the other hand, showed a stronger affinity for neutral flat membranes consisting of methyl-branched lipids. To rationalize these results, we used all-atom molecular dynamics simulations to investigate the influence of methyl-branched lipids on interfacial membrane properties. We found that methyl-branched lipids promote the membrane adsorption of AS by creating shallow lipid-packing defects to a larger extent than polyunsaturated and monounsaturated lipids. Our findings suggest that methyl-branched lipids may constitute a remarkably adhesive substrate for peripheral proteins that adsorb on membranes via hydrophobic insertions.
α-突触核蛋白（AS）是一种突触蛋白，因其易于形成蛋白质聚集体而直接参与帕金森病。由于AS聚集可能依赖于该蛋白与细胞质膜之间的相互作用，阐明AS的膜结合特性对于确立AS聚集成有毒原纤维的分子基础至关重要。通过结合基于巨型单层囊泡（GUVs）的体外重构实验、共聚焦显微镜和全原子分子动力学模拟，我们研究了AS的膜结合特性，重点关注疏水相互作用与静电相互作用的相对贡献。与先前的观察结果相反，我们没有观察到AS与含有神经节苷脂GM1的膜有任何结合，即使在GM1含量相对较高时也是如此。另一方面，AS对由甲基支链脂质组成的中性平面膜表现出更强的亲和力。为了解释这些结果，我们使用全原子分子动力学模拟来研究甲基支链脂质对界面膜性质的影响。我们发现，甲基支链脂质通过比多不饱和和单不饱和脂质更大程度地产生浅脂质堆积缺陷来促进AS的膜吸附。我们的研究结果表明，甲基支链脂质可能构成通过疏水插入吸附在膜上的外周蛋白的一种显著粘性底物。
