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Voltage vs. Ligand II: Structural insights of the intrinsic flexibility in cyclic nucleotide-gated channels.
Channels ( IF 3.3 ) Pub Date : 2019-09-25 , DOI: 10.1080/19336950.2019.1666456
Sergio Romero-Romero 1 , Gustavo Martínez-Delgado 2 , Daniel Balleza 3
Affiliation  

In the preceding article, we present a flexibility analysis of the voltage-gated ion channel (VGIC) superfamily. In this study, we describe in detail the flexibility profile of the voltage-sensor domain (VSD) and the pore domain (PD) concerning the evolution of 6TM ion channels. In particular, we highlight the role of flexibility in the emergence of CNG channels and describe a significant level of sequence similarity between the archetypical VSD and the TolQ proteins. A highly flexible S4-like segment exhibiting Lys instead Arg for these membrane proteins is reported. Sequence analysis indicates that, in addition to this S4-like segment, TolQ proteins also show similarity with specific motifs in S2 and S3 from typical V-sensors. Notably, S3 flexibility profiles from typical VSDs and S3-like in TolQ proteins are also similar. Interestingly, TolQ from early divergent prokaryotes are comparatively more flexible than those in modern counterparts or true V-sensors. Regarding the PD, we also found that 2TM K+-channels in early prokaryotes are considerably more flexible than the ones in modern microbes, and such flexibility is comparable to the one present in CNG channels. Voltage dependence is mainly exhibited in prokaryotic CNG channels whose VSD is rigid whereas the eukaryotic CNG channels are considerably more flexible and poorly V-dependent. The implication of the flexibility present in CNG channels, their sensitivity to cyclic nucleotides and the cation selectivity are discussed. Finally, we generated a structural model of the putative cyclic nucleotide-modulated ion channel, which we coined here as AqK, from the thermophilic bacteria Aquifex aeolicus, one of the earliest diverging prokaryotes known. Overall, our analysis suggests that V-sensors in CNG-like channels were essentially rigid in early prokaryotes but raises the possibility that this module was probably part of a very flexible stator protein of the bacterial flagellum motor complex.



中文翻译:

电压与配体 II:环核苷酸门控通道内在灵活性的结构见解。

在上一篇文章中,我们对电压门控离子通道(VGIC)超家族进行了灵活性分析。在这项研究中,我们详细描述了与 6TM 离子通道演化相关的电压传感器域 (VSD) 和孔域 (PD) 的灵活性概况。我们特别强调了灵活性在 CNG 通道出现中的作用,并描述了典型 VSD 和 TolQ 蛋白之间显着水平的序列相似性。据报道,这些膜蛋白具有高度灵活的类 S4 片段,显示 Lys 而不是 Arg。序列分析表明,除了这个类似 S4 的片段之外,TolQ 蛋白还显示出与典型 V 传感器的 S2 和 S3 中的特定基序的相似性。值得注意的是,典型 VSD 的 S3 灵活性特征和 TolQ 蛋白中的 S3 样特征也相似。有趣的是,来自早期分歧原核生物的 TolQ 比现代同类或真正的 V 传感器更灵活。关于PD,我们还发现早期原核生物中的2TM K +通道比现代微生物中的2TM K + 通道更加灵活,并且这种灵活性与CNG 通道中存在的灵活性相当。电压依赖性主要表现在原核 CNG 通道中,其 VSD 是刚性的,而真核 CNG 通道则更加灵活且 V 依赖性较差。讨论了 CNG 通道中存在的灵活性、它们对环核苷酸的敏感性和阳离子选择性的含义。最后,我们从嗜热细菌Aquifex aeolicus中生成了假定的环核苷酸调节离子通道的结构模型,我们将其命名为 AqK,这是已知最早的分化原核生物之一。总体而言,我们的分析表明,CNG 样通道中的 V 传感器在早期原核生物中本质上是刚性的,但提出了该模块可能是细菌鞭毛运动复合体的非常灵活的定子蛋白的一部分的可能性。

更新日期:2019-09-25
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