Parkinson disease is associated with the aggregation of the protein α-synuclein. While α-synuclein can exist in multiple oligomeric states, the dimer has been a subject of extensive debates. Here, using an array of biophysical approaches, we demonstrate that α-synuclein in vitro exhibits primarily a monomer-dimer equilibrium in nanomolar concentrations and up to a few micromolars. We then use spatial information from hetero-isotopic cross-linking mass spectrometry experiments as restrains in discrete molecular dynamics simulations to obtain the ensemble structure of dimeric species. Out of eight structural sub-populations of dimers, we identify one that is compact, stable, abundant, and exhibits partially exposed β-sheet structures. This compact dimer is the only one where the hydroxyls of tyrosine 39 are in proximity that may promote dityrosine covalent linkage upon hydroxyl radicalization, which is implicated in α-synuclein amyloid fibrils. We propose that this α-synuclein dimer features etiological relevance to Parkinson disease.

帕金森病与蛋白质 α-突触核蛋白的聚集有关。虽然 α-突触核蛋白可以以多种寡聚状态存在，但二聚体一直是广泛争论的主题。在这里，我们使用一系列生物物理方法证明，α-突触核蛋白在体外主要表现出纳摩尔浓度和高达几微摩尔浓度的单体-二聚体平衡。然后，我们使用异同位素交联质谱实验的空间信息作为离散分子动力学模拟的约束，以获得二聚体的整体结构。在二聚体的八个结构亚群中，我们鉴定出一种紧凑、稳定、丰富且表现出部分暴露的β-折叠结构的亚群。这种紧凑的二聚体是唯一一种酪氨酸 39 的羟基接近的二聚体，可以在羟基自由基化时促进二酪氨酸共价连接，这与 α-突触核蛋白淀粉样原纤维有关。我们认为这种 α-突触核蛋白二聚体具有与帕金森病的病因学相关性。