Structures of the E46K mutant-type α-synuclein protein and impact of E46K mutation on the structures of the wild-type α-synuclein protein.
Structures of the E46K mutant-type α-synuclein protein and impact of E46K mutation on the structures of the wild-type α-synuclein protein.
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DOI：
10.1021/cn3002027
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发表时间：
2013-03
影响因子：
5
通讯作者：
Olivia Wise-Scira;Aquila Dunn;A. K. Aloglu;I. T. Sakallioglu;Orkid Coskuner
中科院分区：
文献类型：
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作者：
Olivia Wise-Scira;Aquila Dunn;A. K. Aloglu;I. T. Sakallioglu;Orkid Coskuner
野生型α-突触核蛋白的E46K基因错义突变最近在一个西班牙血统的遗传性帕金森病家族中被发现。详细了解单个E46K突变型α-突触核蛋白的结构，以及E46K错义突变对野生型α-突触核蛋白构象和自由能格局的影响，是深入了解帕金森病发病机制的必要条件。在这项研究中，我们使用了大量的平行回火分子动力学模拟以及热力学计算来评估单体野生型和E46K突变型α-突触核蛋白在水溶液环境中的二级和第三级结构性质以及构象偏好。我们还使用我们最近开发的理论策略提出了带有动力学的剩余二级结构组件转换稳定性。据我们所知，本研究首次在原子水平上详细比较了野生型和E46K突变型α-突触核蛋白在水溶液环境中的结构和热力学性质。我们发现E46K突变不仅会导致野生型α-突触核蛋白结构特性的局部变化，而且会导致其长程变化。E46K突变后，突变位点的螺旋含量显著降低，β-片结构形成显著增加。此外，E46K突变型αS的c端区β-sheet含量明显高于野生型αS。我们为评估二级结构转变的热力学偏好而开发的理论策略表明，二级结构的这种转变是由于转向螺旋转换的热力学偏好减少，而这些残留物的线圈到β-片的偏好增加。E46K突变后，c端与n端和NAC区域的分子内蛋白相互作用增加，导致突变型E46K比野生型αS结构更紧凑。然而，E46K突变型αS结构的稳定性不如野生型αS。总的来说，我们的研究结果表明，E46K突变型αS比野生型αS具有更高的聚集倾向，并且在E46K突变后，n端和c端区域对成纤维和聚集具有反应性，我们根据结构性质解释了相关原因。小分子或药物可以阻断特定残基形成丰富的β-片结构，我们在这里报道，可能有助于降低这些内在无序的纤维原蛋白对聚集及其毒性的反应性。
The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type α-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in β-sheet structure formation upon E46K mutation. In addition, the β-sheet content of the C-terminal region increases significantly in the E46K mutant-type αS in comparison to the wild-type αS. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to β-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type αS. However, the E46K mutant-type αS structures are less stable than the wild-type αS. Overall, our results show that the E46K mutant-type αS has a higher propensity to aggregate than the wild-type αS and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant β-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.