Structure and membrane binding of alpha-synuclein

α-突触核蛋白(AS)是一种小的突触前蛋白，与帕金森病的发病机制有关。它在本质上无序的胞浆状态和更有结构的囊泡结合状态之间进行划分。到目前为止，对S的结构研究主要基于十二烷基硫酸钠与洗涤剂结合的条件，在该条件下，S在N-末端区域显示-螺旋，在溶液中保持自由的非结构化C-末端尾巴。我们研究了在脂双分子存在下S的结构和生物物理性质。脂双分子具有天然脂双层的优点，同时还具有小的囊泡半径，这使得它们适合于溶液核磁共振研究。我们的生物物理和核磁共振数据表明，S对酸性和两性离子类脂头基团的特定组合表现出偏好，并证明S参与了脂双分子层上的动态交换过程，这种交换过程可能会随着时间的推移而重组。此外，我们的结果表明，S的这种脂质相互作用与聚集倾向的影响是耦合的。对于全长的S来说，脂双分子极大地促进了聚集，产生了有序的纤维结构。对于突触核蛋白的C末端缺失结构，脂质诱导的聚集甚至被更强烈地刺激。

Alpha-synuclein (aS) is a small presynaptic protein implicated in the pathogenesis of Parkinsons disease. It partitions between an intrinsically disordered cytosolic state and a more structured vesicle-bound state. Structural studies of αS have, to date, been based largely on the SDS detergent-bound conditions, for which αS displays α-helices in the N-terminal domain and an unstructured C-terminal tail that remains free in solution. We have investigated the structure and biophysics of αS in the presence of lipid bicelles. Lipid bicelles offer the advantage of a natural lipid bilayer while also featuring small vesicle radii which render them amenable to solution NMR studies. Our biophysical and NMR data show that αS displays a preference for specific combinations of acidic and zwitterionic lipid headgroups and give evidence that αS participates in dynamic exchange processes on the lipid bilayer that may reorganize the bilayer with time. Additionally, our results show that this lipid interaction of αS is coupled with effects on aggregation propensity. For full length αS, lipid bicelles greatly enhance aggregation, producing well-ordered, fibrillar structures. The lipid-induced aggregation is even more strongly stimulated for a C-terminal deletion construct of α-synuclein.