Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France.
Int J Mol Sci. 2022 Jan 21;23(3):1175. doi: 10.3390/ijms23031175.
The voltage-dependent anion channel 1 (VDAC1) is a crucial mitochondrial transporter that controls the flow of ions and respiratory metabolites entering or exiting mitochondria. As a voltage-gated channel, VDAC1 can switch between a high-conducting "open" state and a low-conducting "closed" state emerging at high transmembrane (TM) potentials. Although cell homeostasis depends on channel gating to regulate the transport of ions and metabolites, structural hallmarks characterizing the closed states remain unknown. Here, we performed microsecond accelerated molecular dynamics to highlight a vast region of VDAC1 conformational landscape accessible at typical voltages known to promote closure. Conformers exhibiting durable subconducting properties inherent to closed states were identified. In all cases, the low conductance was due to the particular positioning of an unfolded part of the N-terminus, which obstructed the channel pore. While the N-terminal tail was found to be sensitive to voltage orientation, our models suggest that stable low-conducting states of VDAC1 predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. In addition, our results were consistent with conductance jumps observed experimentally and corroborated a recent study describing entropy as a key factor for VDAC gating.
电压依赖性阴离子通道 1（VDAC1）是一种至关重要的线粒体转运蛋白，它控制着离子和呼吸代谢物进出线粒体的流动。作为一种电压门控通道，VDAC1 可以在高跨膜（TM）电位下在高电导“开放”状态和低电导“关闭”状态之间切换。尽管细胞内稳态依赖于通道门控来调节离子和代谢物的运输，但表征关闭状态的结构特征仍然未知。在这里，我们进行了微秒加速分子动力学模拟，以突出在典型电压下可访问的 VDAC1 构象景观的广阔区域，这些电压已知可促进关闭。鉴定出具有关闭状态固有持久亚电导特性的构象体。在所有情况下，低电导是由于 N 端未折叠部分的特定定位，该部分阻塞了通道孔。虽然发现 N 端尾部对电压方向敏感，但我们的模型表明，VDAC1 的稳定低电导状态主要来自无序事件，而不是由于电压传感器的位移或孔的显著变化。此外，我们的结果与实验中观察到的电导跃变一致，并证实了最近的一项研究，该研究将熵描述为 VDAC 门控的关键因素。
