Structure and membrane binding of alpha-synuclein

α -突触核蛋白（aS）是一种与帕金森病发病机制有关的小突触前蛋白。它在本质上无序的细胞质状态和更有结构的囊泡结合状态之间分裂。过去对aS的结构研究主要是基于SDS洗涤剂结合的条件，其中aS在n端区域显示两个α -螺旋，在溶液中显示一个非结构化的c端尾部。我们研究了磷脂囊泡存在时aS的结构和生物物理学，磷脂囊泡模仿突触前囊泡的膜组成。对磷脂的亲和力非常高，通过核磁共振测量，产生亲和力Kd为50 uM，这强烈表明在细胞环境中，蛋白质将在膜结合状态下达到99.9%。转移NOE实验表明，该蛋白在膜结合状态下呈高度螺旋状，与先前的实验数据相反，c端40残基也参与了与膜的直接相互作用。可以区分出四种不同的膜结合模式，其相对数量取决于aS：脂质摩尔比。其中一种结合模式与纤维的加速形成有关。

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. Past structural studies of aS have been based largely on the SDS detergent-bound conditions, for which aS displays two alpha-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 aS in the presence of phospholipid vesicles that mimic the membrane composition of presynaptic vesicles. Very high affinity for phospholipids is measured by NMR, yielding an affinity Kd of 50 uM, which strongly suggests that in the cellular environment the protein will be >99.9% in the membrane bound state. Transferred NOE experiments indicate that the protein is highly helical in the membrane bound state, and that in contrast to prior experimental data, the C-terminal 40 residues also participate in direct interactions with the membrane. Four distinct binding modes with the membrane can be distinguished, whose relative populations depend on the aS:lipid molar ratio. One of these binding modes is implicated in accelerated fibril formation.