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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >Gating of Connexin Channels by transjunctional-voltage: Conformations and models of open and closed states
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Gating of Connexin Channels by transjunctional-voltage: Conformations and models of open and closed states

机译：通过Transjunction-电压键入Connexin通道：打开和封闭状态的构象和模型

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Abstract Voltage is an important physiologic regulator of channels formed by the connexin gene family. Connexins are unique among ion channels in that both plasma membrane inserted hemichannels (undocked hemichannels) and intercellular channels (aggregates of which form gap junctions) have important physiological roles. The hemichannel is the fundamental unit of gap junction voltage-gating. Each hemichannel displays two distinct voltage-gating mechanisms that are primarily sensitive to a voltage gradient formed along the length of the channel pore (the transjunctional voltage) rather than sensitivity to the absolute membrane potential (V m or V i-o ). These transjunctional voltage dependent processes have been termed V j - or fast-gating and loop- or slow-gating. Understanding the mechanism of voltage-gating, defined as the sequence of voltage-driven transitions that connect open and closed states, first and foremost requires atomic resolution models of the end states. Although ion channels formed by connexins were among the first to be characterized structurally by electron microscopy and x-ray diffraction in the early 1980′s, subsequent progress has been slow. Much of the current understanding of the structure-function relations of connexin channels is based on two crystal structures of Cx26 gap junction channels. Refinement of crystal structure by all-atom molecular dynamics and incorporation of charge changing protein modifications has resulted in an atomic model of the open state that arguably corresponds to the physiologic open state. Obtaining validated atomic models of voltage-dependent closed states is more challenging, as there are currently no methods to solve protein structure while a stable voltage gradient is applied across the length of an oriented channel. It is widely believed that the best approach to solve the atomic structure of a voltage-gated closed ion channel is to apply different but complementary experimental and computational methods and to use the resulting information to derive a consensus atomic structure that is then subjected to rigorous validation. In this paper, we summarize our efforts to obtain and validate atomic models of the open and voltage-driven closed states of undocked connexin hemichannels. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. Highlights ? Connexin channels have two distinct voltage-gating mechanisms: loop- and V j -gating. ? Understanding voltage-gating requires atomic models of end states. ? Atomic models of the physiological open state have been created and validated. ? Metal bridging has defined the conformation of the loop-gate closed state. ? The distance constraints provide closed state atomic models. ? Strategies to further refine and validate atomic models are discussed.
机译：摘要电压是由Connexin基因家族形成的通道的重要生理调节器。 Connexins在离子通道中是独特的，因为离子通道中的两个血浆膜插入血管膜（未缓解的血管）和细胞间通道（其形式间隙结的聚集体）具有重要的生理作用。 Hemimannel是间隙结电压门的基本单元。每个HemiCannel显示两个不同的电压 - 门控机构，其主要敏感于沿着通道孔的长度（传递电压）的长度而不是对绝对膜电位的敏感性（V M或V I-O）形成的电压梯度。这些跨界电压相关过程已被称为V J - 或快速门控和环路或慢栅。了解电压门控机制，定义为连接打开和闭合状态的电压驱动的转变序列，首先是结束状态的原子分辨率模型。尽管由Connexins形成的离子通道是第一个通过电子显微镜和X射线衍射在1980年代早期在结构上表征，但随后的进展缓慢。目前对Connexin通道的结构功能关系的大部分理解基于CX26间隙结沟道的两个晶体结构。通过全原子分子动力学和电荷变化蛋白质修饰的掺入的晶体结构的改进导致打开状态的原子模型，可谓对应于生理开放状态。获得验证的电压依赖性闭合状态的原子模型更具挑战性，因为目前没有解决蛋白质结构的方法，而在取向通道的长度上施加稳定的电压梯度。众所周知，解决电压门控封闭离子通道的原子结构的最佳方法是应用不同但互补的实验和计算方法，并使用所得信息来导出与经过严格的验证的共识原子结构。在本文中，我们总结了我们努力获得和验证未缓解Connexin血管内的开放和电压驱动的闭合状态的原子模型。本文是题为的特殊问题的一部分：Jean Claude Herve编辑的Gap Junction蛋白。强调 ？ Connexin通道具有两个不同的电压 - 门控机构：环路和v j -gating。还理解电压门控需要终端状态的原子模型。还已经创建和验证了生理开放状态的原子模型。还金属桥接限定了环路闸门关闭状态的构造。还距离约束提供闭合状态原子模型。还讨论了进一步优化和验证原子模型的策略。

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