Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics
Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics
复制标题
DOI：
10.1021/cn400066t
复制
发表时间：
2013-10-01
影响因子：
5
通讯作者：
Sparr, Emma
中科院分区：
文献类型：
--
作者：
Hellstrand, Erik;Grey, Marie;Sparr, Emma
α-突触核蛋白的淀粉样蛋白形式是称为路易体的神经元内包涵体的主要成分，路易体是帕金森病（PD）的神经病理学标志。已知α-突触核蛋白与阴离子脂质膜缔合，并且聚集的α-突触核蛋白与细胞膜之间的相互作用被认为对于PD病理学是重要的。我们已经研究了单体α-突触核蛋白吸附到由两性离子磷脂酰胆碱单独或与阴离子磷脂酰丝氨酸（质膜相关）或阴离子心磷脂（线粒体膜相关）的混合物组成的平面模型脂质膜的分子决定因素。我们研究了蛋白质的吸附支持双层，蛋白质的位置内和外的双层，和结构变化的模型膜使用两个互补的技术-石英晶体微天平与耗散监测，和中子反射仪。我们发现，相互作用和吸附构象依赖于膜电荷，蛋白质电荷，和静电屏蔽。结果表明，α-突触核蛋白吸附在头基区域的阴离子脂质双层延伸到散装，但不深入渗透到或跨越疏水酰基链区域。吸附到阴离子双层导致的酰基链包装，这是独立的阴离子头基身份的小扰动。我们还探讨了通过比较具有不同程度的酰基链饱和度的模型系统来改变脂质双层中每个头基的面积的效果。每个脂质头基面积的增加导致α-突触核蛋白吸附水平的增加，同时酰基链层中的水含量降低。总之，α-突触核蛋白与膜的结合及其吸附构象是静电起源的，结合了货车德瓦尔斯相互作用，但与阴离子脂质头基的分子结构的相关性非常弱。在单体蛋白质吸附后酰基链包装的扰动有利于与优先在神经元膜中发现的不饱和磷脂缔合。
An amyloid form of the protein alpha-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). alpha-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating alpha-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric alpha-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniques-quartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that alpha-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of alpha-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of alpha-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.