Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
Structure. 2023 Apr 6;31(4):411-423.e6. doi: 10.1016/j.str.2023.01.011. Epub 2023 Feb 20.
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-突触核蛋白可以存在于多种寡聚状态，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-突触核蛋白在纳米摩尔浓度下主要表现为单体-二聚体平衡，直到几微摩尔。然后，我们使用来自异质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条件，以获得二聚体物种的整体结构。在八个二聚体结构亚群中，我们确定了一种紧凑、稳定、丰富且部分暴露β-折叠结构的二聚体。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，可能在羟基自由基化时促进二酪氨酸共价键合，这与α-突触核蛋白淀粉样纤维有关。我们提出，这种α-突触核蛋白二聚体具有帕金森病的病因学相关性。
