Investigating the Mechanism of Substrate Uptake and Release in the Glutamate Transporter Homologue GltPh through Metadynamics Simulations
Investigating the Mechanism of Substrate Uptake and Release in the Glutamate Transporter Homologue GltPh through Metadynamics Simulations
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DOI：
10.1021/ja208485w
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发表时间：
2012-01-11
影响因子：
15
通讯作者：
Parrinello, Michele
中科院分区：
文献类型：
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作者：
Grazioso, Giovanni;Limongelli, Vittorio;Parrinello, Michele
突触间隙内谷氨酸的稳态浓度确保了沿着神经元网络的正确信号转导。谷氨酸转运体在这方面起着至关重要的作用，因为它们负责从突触间隙重新摄取神经递质，从而控制谷氨酸浓度。了解这种转运蛋白的分子机制可以提供外源调控的可能性。结构研究表明，这种转运蛋白至少可以有三种构象，从而表明了一种明显的动力学行为。然而，导致底物内化的一些中间状态还没有被表征，转运蛋白机制的许多方面仍然不清楚。在这里，使用元动力学模拟，我们研究了底物从突触裂隙摄取和它在细胞内介质中的释放。此外，我们还重点研究了离子和底物在这些过程中的作用，以及转运蛋白所承担的不同构象的稳定性。目前的动力学结果可以补充现有的X射线数据，并提供了底物摄取、内化和释放的整个过程的完整描述。
A homeostatic concentration of glutamate in the synaptic cleft ensures a correct signal transduction along the neuronal network. An unbalance in this concentration can lead to neuronal death and to severe neurodegenerative diseases such as Alzheimer's or Parkinson's. Glutamate transporters play a crucial role in this respect because they are responsible for the reuptake of the neurotransmitter from the synaptic cleft, thus controlling the glutamate concentration. Understanding the molecular mechanism of this transporter can provide the possibility of an exogenous control. Structural studies have shown that this transporter can assume at least three conformations, thus suggesting a pronounced dynamical behavior. However, some intermediate states that lead to the substrate internalization have not been characterized and many aspects of the transporter mechanism still remain unclear. Here, using metadynamics simulations, we investigate the substrate uptake from the synaptic cleft and its release in the intracellular medium. In addition, we focus on the role of ions and substrate during these processes and on the stability of the different conformations assumed by the transporter. The present dynamical results can complement available X-ray data and provide a thorough description of the entire process of substrate uptake, internalization, and release.