Biozentrum, University of Basel, Basel 4056, Switzerland.
Life Science and Health, Jacobs University Bremen, Bremen 28759, Germany.
Structure. 2020 Feb 4;28(2):206-214.e4. doi: 10.1016/j.str.2019.11.015. Epub 2019 Dec 17.
The voltage-dependent anion channel (VDAC) forms the primary diffusion pore of the outer mitochondrial membrane. In its apo form, VDAC adopts an open conformation with high conductance. States of lower conductance can be induced by ligand binding or the application of voltage. Here, we clarify at the atomic level how β-NADH binding leads to a low-conductance state and characterize the role of the VDAC N-terminal helix in voltage gating. A high-resolution NMR structure of human VDAC-1 with bound NADH, combined with molecular dynamics simulation show that β-NADH binding reduces the pore conductance sterically without triggering a structural change. Electrophysiology recordings of crosslinked protein variants and NMR relaxation experiments probing different time scales show that increased helix dynamics is present in the open state and that motions of the N-terminal helices are involved in the VDAC voltage gating mechanism.
电压依赖性阴离子通道（VDAC）形成了外线粒体膜的主要扩散孔道。在apo 形式下，VDAC 采用具有高电导率的开放构象。配体结合或施加电压可以诱导电导率降低的状态。在这里，我们在原子水平上阐明了 β-NADH 结合如何导致低电导状态，并表征了 VDAC N 端螺旋在电压门控中的作用。与结合 NADH 的人 VDAC-1 的高分辨率 NMR 结构，结合分子动力学模拟表明，β-NADH 结合通过空间位阻降低了孔道的电导率，而不会引发结构变化。交联蛋白变体的电生理学记录和探测不同时间尺度的 NMR 弛豫实验表明，在开放状态下存在增加的螺旋动力学，并且 N 端螺旋的运动参与了 VDAC 电压门控机制。
