Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain
Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain
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DOI：
10.1038/nature02588
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发表时间：
2004-06-10
期刊：
影响因子：
64.8
通讯作者：
Minor, DL
中科院分区：
文献类型：
--
作者：
Van Petegem, F;Clark, KA;Minor, DL
电压门控钙通道（CaV）控制肌肉收缩、激素和神经递质释放、神经元迁移、钙依赖性信号级联的激活和突触输入整合（1）。一种必需的Ca-V细胞内蛋白，β亚基（Ca（V）β）（1，2），结合一个保守结构域（α-相互作用结构域，AID），并深刻地影响多个通道特性，如电压依赖性激活（2），失活速率（2），G蛋白调节（4），药物敏感性（5）和细胞表面表达（6，7）。在这里，我们报告的高分辨率晶体结构的Ca（V）β（2a）保守的核心，单独和复杂的AID。先前的工作表明，保守区域，β-相互作用结构域（BID），形成了艾滋病结合位点（3，8）;然而，该区域主要埋在Ca（V）β核心，是不可用的蛋白质-蛋白质相互作用。AID-Ca（V）β（2a）复合物的结构显示，Ca（V）β（2a）通过广泛的保守疏水裂缝（称为α结合口袋，ABP）与AID结合。ABP - AID相互作用将Ca（V）β的一端定位在称为IS 6的孔衬段的细胞内端附近，IS 6在Ca-V失活中具有关键作用（9，10）。总之，这些数据表明Ca（V）β通过直接调节通道孔内的IS 6运动来影响Ca-V门控。
Voltage-gated calcium channels (CaVs) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration(1). An essential Ca-V intracellular protein, the beta-subunit (Ca(V)beta)(1,2), binds a conserved domain ( the alpha-interaction domain, AID) between transmembrane domains I and II of the pore-forming alpha(1) subunit(3) and profoundly affects multiple channel properties such as voltage-dependent activation(2), inactivation rates(2), G-protein modulation(4), drug sensitivity(5) and cell surface expression(6,7). Here, we report the high-resolution crystal structures of the Ca(V)beta(2a) conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the beta-interaction domain (BID), formed the AID-binding site(3,8); however, this region is largely buried in the Ca(V)beta core and is unavailable for protein - protein interactions. The structure of the AID - Ca(V)beta(2a) complex shows instead that Ca(V)beta(2a) engages the AID through an extensive, conserved hydrophobic cleft ( named the alpha-binding pocket, ABP). The ABP - AID interaction positions one end of the Ca(V)beta near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca-V inactivation(9,10). Together, these data suggest that Ca(V)betas influence Ca-V gating by direct modulation of IS6 movement within the channel pore.