Department of Cell Biology, University of Massachusetts Medical School, MA, USA.
Mol Biol Evol. 2012 Sep;29(9):2147-55. doi: 10.1093/molbev/mss083. Epub 2012 Mar 6.
The voltage-sensitive phosphoinositide phosphatases provide a mechanism to couple changes in the transmembrane electrical potential to intracellular signal transduction pathways. These proteins share a domain architecture that is conserved in deuterostomes. However, gene duplication events in primates, including humans, give rise to the paralogs TPTE and TPTE2 that retain protein domain organization but, in the case of TPTE, have lost catalytic activity. Here, we present evidence that these human proteins contain a functional voltage sensor, similar to that in nonmammalian orthologs. However, domains of these human proteins can also generate a noninactivating outward current that is not observed in zebra fish or tunicate orthologs. This outward current has the anticipated characteristics of a voltage-sensitive proton current and is due to the appearance of a single histidine residue in the S4 transmembrane segment of the voltage sensor. Histidine is observed at this position only during the eutherian radiation. Domains from both human paralogs generate proton currents. This apparent gain of proton channel function during the evolution of the TPTE protein family may account for the conservation of voltage sensor domains despite the loss of phosphatase activity in some human paralogs.
电压敏感性磷酯酶提供了一种将跨膜电势能变化与细胞内信号转导途径偶联的机制。这些蛋白具有保守的结构域架构，在后口动物中存在。然而，灵长类动物（包括人类）中的基因复制事件导致了 TPTE 和 TPTE2 的出现，这些蛋白保留了蛋白结构域组织，但在 TPTE 的情况下失去了催化活性。在这里，我们提供的证据表明，这些人类蛋白包含一个功能电压传感器，类似于非哺乳动物的同源物。然而，这些人类蛋白的结构域也可以产生一种非失活的外向电流，而在斑马鱼或被囊动物的同源物中没有观察到这种电流。这种外向电流具有预期的电压敏感质子电流的特征，是由于电压传感器 S4 跨膜片段中的单个组氨酸残基的出现。在这个位置只有在真兽类辐射期间才会观察到组氨酸。来自人类两个同源物的结构域都产生质子电流。在 TPTE 蛋白家族的进化过程中，质子通道功能的这种明显获得可能解释了尽管某些人类同源物失去了磷酸酶活性，但电压传感器结构域仍然存在的原因。
