Tecnológico Nacional de México, Instituto Tecnológico de Veracruz, Unidad de Investigación y Desarrollo en Alimentos, Calz. Miguel Angel de Quevedo 2779, Col. Formando Hogar, CP. 91897, Veracruz, Ver, Mexico.
J Mol Evol. 2023 Dec;91(6):819-836. doi: 10.1007/s00239-023-10140-1. Epub 2023 Nov 13.
The voltage-sensing domain (VSD) is a module capable of responding to changes in the membrane potential through conformational changes and facilitating electromechanical coupling to open a pore gate, activate proton permeation pathways, or promote enzymatic activity in some membrane-anchored phosphatases. To carry out these functions, this module acts cooperatively through conformational changes. The VSD is formed by four transmembrane segments (S1-S4) but the S4 segment is critical since it carries positively charged residues, mainly Arg or Lys, which require an aqueous environment for its proper function. The discovery of this module in voltage-gated ion channels (VGICs), proton channels (Hv1), and voltage sensor-containing phosphatases (VSPs) has expanded our understanding of the principle of modularity in the voltage-sensing mechanism of these proteins. Here, by sequence comparison and the evaluation of the relationship between sequence composition, intrinsic flexibility, and structural analysis in 14 selected representatives of these three major protein groups, we report five interesting differences in the folding patterns of the VSD both in prokaryotes and eukaryotes. Our main findings indicate that this module is highly conserved throughout the evolutionary scale, however: (1) segments S1 to S3 in eukaryotes are significantly more hydrophobic than those present in prokaryotes; (2) the S4 segment has retained its hydrophilic character; (3) in eukaryotes the extramembranous linkers are significantly larger and more flexible in comparison with those present in prokaryotes; (4) the sensors present in the kHv1 proton channel and the ciVSP phosphatase, both of eukaryotic origin, exhibit relationships of flexibility and folding patterns very close to the typical ones found in prokaryotic voltage sensors; and (5) archaeal channels KvAP and MVP have flexibility profiles which are clearly contrasting in the S3-S4 region, which could explain their divergent activation mechanisms. Finally, to elucidate the obscure origins of this module, we show further evidence for a possible connection between voltage sensors and TolQ proteins.
电压传感器域（VSD）是一种能够通过构象变化响应膜电位变化并促进机电偶联以打开孔门、激活质子渗透途径或促进某些膜锚定磷酸酶的酶活性的模块。为了执行这些功能，该模块通过构象变化协同作用。VSD 由四个跨膜片段（S1-S4）组成，但 S4 片段是关键的，因为它携带带正电荷的残基，主要是精氨酸或赖氨酸，这些残基需要水相环境才能正常发挥作用。该模块在电压门控离子通道（VGICs）、质子通道（Hv1）和含电压传感器的磷酸酶（VSPs）中的发现，扩展了我们对这些蛋白质的电压感应机制中模块性原理的理解。在这里，通过序列比较以及对 14 个这三个主要蛋白质组的代表性序列组成、固有灵活性和结构分析之间关系的评估，我们报告了在原核生物和真核生物中 VSD 折叠模式的五个有趣差异。我们的主要发现表明，该模块在整个进化尺度上都高度保守，然而：（1）真核生物的 S1 到 S3 段比原核生物的更疏水；（2）S4 段保留了其亲水性；（3）与原核生物相比，真核生物的跨膜连接子明显更大且更灵活；（4）源自真核生物的 kHv1 质子通道和 ciVSP 磷酸酶中的传感器表现出与在原核电压传感器中发现的典型传感器非常接近的灵活性和折叠模式关系；（5）古细菌通道 KvAP 和 MVP 在 S3-S4 区域具有明显对比的灵活性特征，这可以解释它们不同的激活机制。最后，为了阐明该模块的模糊起源，我们进一步展示了电压传感器和 TolQ 蛋白之间可能存在联系的证据。
