Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA.
Int J Mol Sci. 2021 Jul 8;22(14):7358. doi: 10.3390/ijms22147358.
The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two otherwise unrelated cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics-reduced metabolite flux and increased calcium flux-are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC.
电压依赖性阴离子通道（VDAC）是水可溶性代谢物和离子穿过线粒体外膜的主要调节途径。当重组到脂质膜中时，VDAC 会对足够大的跨膜电位做出反应，转变为门控状态，在此状态下，ATP/ADP 通量降低，钙通量增加。两种原本不相关的胞质溶胶蛋白，微管蛋白和α-突触核蛋白（αSyn），通过一种新的机制与 VDAC 结合，在这种机制中，跨膜电位将它们无序的、多阴离子的 C 端结构域拉入并穿过 VDAC 通道，从而物理上阻塞了孔道。对于微管蛋白和 αSyn 来说，在比 VDAC 门控状态低得多的跨膜电位下观察到阻塞状态，因此在这些胞质溶胶 docking 蛋白存在的情况下，VDAC 对跨膜电位的敏感性大大增加。值得注意的是，由两种 docking 蛋白诱导的阻塞状态保留了与生物能量学相关的 VDAC 门控状态的特征，即减少代谢物通量和增加钙通量。微管蛋白和 αSyn 调节线粒体电位和体内 ATP 产生的能力现在得到了许多研究的支持。微管蛋白和 αSyn 与 VDAC 相互作用的共同物理起源导致了 VDAC 抑制剂的一般模型，有助于预测已知抑制剂的翻译后修饰的影响，并为开发针对 VDAC 的新型治疗方法指明了方向。
