Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Structure. 2012 Sep 5;20(9):1540-9. doi: 10.1016/j.str.2012.06.015. Epub 2012 Jul 26.
The voltage-dependent anion channel (VDAC) is the major protein in the outer mitochondrial membrane, where it mediates transport of ATP and ADP. Changes in its permeability, induced by voltage or apoptosis-related proteins, have been implicated in apoptotic pathways. The three-dimensional structure of VDAC has recently been determined as a 19-stranded β-barrel with an in-lying N-terminal helix. However, its gating mechanism is still unclear. Using solid-state NMR spectroscopy, molecular dynamics simulations, and electrophysiology, we show that deletion of the rigid N-terminal helix sharply increases overall motion in VDAC's β-barrel, resulting in elliptic, semicollapsed barrel shapes. These states quantitatively reproduce conductance and selectivity of the closed VDAC conformation. Mutation of the N-terminal helix leads to a phenotype intermediate to the open and closed states. These data suggest that the N-terminal helix controls entry into elliptic β-barrel states which underlie VDAC closure. Our results also indicate that β-barrel channels are intrinsically flexible.
电压依赖性阴离子通道（VDAC）是线粒体外膜的主要蛋白，在那里它介导 ATP 和 ADP 的运输。其通透性的变化，由电压或凋亡相关蛋白诱导，与凋亡途径有关。VDAC 的三维结构最近已被确定为 19 股β桶，带有内部 N 端螺旋。然而，其门控机制尚不清楚。使用固态 NMR 光谱、分子动力学模拟和电生理学，我们表明，刚性 N 端螺旋的缺失会显着增加 VDACβ桶的整体运动，导致椭圆、半塌陷的桶形。这些状态定量再现了封闭 VDAC 构象的电导率和选择性。N 端螺旋的突变导致介于开放和关闭状态之间的表型。这些数据表明，N 端螺旋控制着进入椭圆β桶状态，这是 VDAC 关闭的基础。我们的结果还表明，β桶通道本质上是灵活的。
