Protein Folding and Dynamics Laboratory, Structural Biology and Bioinformatics Division , CSIR-Indian Institute of Chemical Biology , Kolkata 700032 , India.
ACS Chem Neurosci. 2019 Mar 20;10(3):1300-1310. doi: 10.1021/acschemneuro.8b00393. Epub 2019 Jan 23.
The aggregation of α-synuclein (α-Syn) has been implicated strongly in Parkinson's disease (PD). The intrinsically disordered nature of α-Syn makes this protein prone to self-association or heteroassociation with another protein or lipid. While conformational fluctuation and free radical chemistry have been shown to play important roles in its ability toward self- and heteroassociation, any systematic understanding of their contributions is missing. Here, we report an in vitro investigation of the interaction between α-Syn and cytochrome c in the oxidized (cyt c III) and reduced forms (cyt c II), in which cyt c III was found to induce a large compaction of α-Syn and inhibit the aggregation by favoring a hetero-dityrosine bond formation. In contrast, the presence of cyt c II did not result in any compaction and its presence was found to facilitate α-Syn aggregation. The variation in the charge distribution of the surface residues of cyt c III and cyt c II is expected to play a decisive role in their interaction with α-Syn.
α-突触核蛋白（α-Syn）的聚集强烈暗示了帕金森病（PD）的发生。α-Syn 的无规则结构性质使其容易与另一种蛋白质或脂质发生自我关联或异源关联。虽然构象波动和自由基化学已被证明在其自我和异源关联能力中起着重要作用，但对它们的贡献仍缺乏系统的理解。在这里，我们报告了体外研究α-Syn 与细胞色素 c 在氧化（cyt c III）和还原形式（cyt c II）之间相互作用的实验，结果发现 cyt c III 诱导了α-Syn 的大规模紧缩，并通过有利于异源二酪氨酸键形成来抑制聚集。相比之下，cyt c II 的存在并没有导致任何紧缩，并且发现它的存在促进了α-Syn 的聚集。预计细胞色素 c III 和 cyt c II 表面残基的电荷分布变化将在它们与α-Syn 的相互作用中发挥决定性作用。
