Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits.
Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits.
复制标题
挖掘蛋白质进化以深入了解电压依赖性钠通道辅助亚基的机制。
DOI：
10.1007/164_2017_75
复制
发表时间：
2018
影响因子：
--
通讯作者：
Ahern,ChristopherA
中科院分区：
文献类型：
--
作者：
Molinarolo,Steven;Granata,Daniele;Carnevale,Vincenzo;Ahern,ChristopherA
电压门控钠通道 (VGSC) β (β) 亚基被称为“超常”辅助离子通道亚基。事实上，这些亚基调节钠通道复合物在质膜上的运输，同时调节成孔α亚基的电压依赖性特性。现在已知 VGSC β 亚基能够对相关电压门控钾通道的多种亚型进行类似的调节，这表明它们的能力扩展到更广泛的电压门控通道。这些单跨膜免疫球蛋白 β 折叠蛋白的基因家族远远超出了传统的 VGSC β1-β4 亚基名称，深深扎根于细胞粘附蛋白家族和髓磷脂相关蛋白，其中遗传突变导致多种电信号传导障碍。然而，人们对 VGSC β 亚基如何支持蛋白质运输途径、其电压依赖性门控调节的基础以及最终在塑造神经元兴奋性中的作用知之甚少。进化方法可用于产生此类功能的新线索，因为它提供了对蛋白质残基、折叠和功能的公正评估。这里描述的一种方法表明，大约 4 亿年前，现代 β 亚基在两侧对称动物和硬骨鱼的早期神经元中大量出现，并且噬菌体中意外地存在遥远的同源物。最近包含含有亚基的α和β真核钠通道的结构突破表明，跨膜片段内发生的高度保守的极性接触具有新的作用。总的来说，多种方法的结合最终将促进我们对 β 亚基与含有离子通道和膜蛋白的电压传感器相互作用机制的理解。
Voltage-gated sodium channel (VGSC) beta (β) subunits have been called the “overachieving” auxiliary ion channel subunit. Indeed, these subunits regulate the trafficking of the sodium channel complex at the plasma membrane and simultaneously tune the voltage-dependent properties of the pore-forming alpha-subunit. It is now known that VGSC β-subunits are capable of similar modulation of multiple isoforms of related voltage-gated potassium channels, suggesting that their abilities extend into the broader voltage-gated channels. The gene family for these single transmembrane immunoglobulin beta-fold proteins extends well beyond the traditional VGSC β1–β4 subunit designation, with deep roots into the cell adhesion protein family and myelin-related proteins – where inherited mutations result in a myriad of electrical signaling disorders. Yet, very little is known about how VGSC β-subunits support protein trafficking pathways, the basis for their modulation of voltage-dependent gating, and, ultimately, their role in shaping neuronal excitability. An evolutionary approach can be useful in yielding new clues to such functions as it provides an unbiased assessment of protein residues, folds, and functions. An approach is described here which indicates the greater emergence of the modern β-subunits roughly 400 million years ago in the early neurons of Bilateria and bony fish, and the unexpected presence of distant homologues in bacteriophages. Recent structural breakthroughs containing α and β eukaryotic sodium channels containing subunits suggest a novel role for a highly conserved polar contact that occurs within the transmembrane segments. Overall, a mixture of approaches will ultimately advance our understanding of the mechanism for β-subunit interactions with voltage-sensor containing ion channels and membrane proteins.