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电压门控 Na+/H+交换器的结构与机电耦联

Structure and electromechanical coupling of a voltage-gated Na/H exchanger.

机构信息

Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.

出版信息

Nature. 2023 Nov;623(7985):193-201. doi: 10.1038/s41586-023-06518-2. Epub 2023 Oct 25.

DOI:10.1038/s41586-023-06518-2
PMID:37880360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10620092/
Abstract

Voltage-sensing domains control the activation of voltage-gated ion channels, with a few exceptions. One such exception is the sperm-specific Na/H exchanger SLC9C1, which is the only known transporter to be regulated by voltage-sensing domains. After hyperpolarization of sperm flagella, SLC9C1 becomes active, causing pH alkalinization and CatSper Ca channel activation, which drives chemotaxis. SLC9C1 activation is further regulated by cAMP, which is produced by soluble adenyl cyclase (sAC). SLC9C1 is therefore an essential component of the pH-sAC-cAMP signalling pathway in metazoa, required for sperm motility and fertilization. Despite its importance, the molecular basis of SLC9C1 voltage activation is unclear. Here we report cryo-electron microscopy (cryo-EM) structures of sea urchin SLC9C1 in detergent and nanodiscs. We show that the voltage-sensing domains are positioned in an unusual configuration, sandwiching each side of the SLC9C1 homodimer. The S4 segment is very long, 90 Å in length, and connects the voltage-sensing domains to the cytoplasmic cyclic-nucleotide-binding domains. The S4 segment is in the up configuration-the inactive state of SLC9C1. Consistently, although a negatively charged cavity is accessible for Na to bind to the ion-transporting domains of SLC9C1, an intracellular helix connected to S4 restricts their movement. On the basis of the differences in the cryo-EM structure of SLC9C1 in the presence of cAMP, we propose that, upon hyperpolarization, the S4 segment moves down, removing this constriction and enabling Na/H exchange.

摘要

电压感应结构域控制着电压门控离子通道的激活，但也有一些例外。一个这样的例外是精子特异性 Na/H 交换器 SLC9C1，它是唯一已知的受电压感应结构域调节的转运体。在精子鞭毛超极化后，SLC9C1 变得活跃，导致 pH 值碱化和 CatSper Ca 通道激活，从而驱动趋化性。SLC9C1 的激活进一步受到 cAMP 的调节，cAMP 由可溶性腺苷酸环化酶 (sAC) 产生。因此，SLC9C1 是后生动物 pH-sAC-cAMP 信号通路的重要组成部分，对于精子运动和受精是必需的。尽管它很重要，但 SLC9C1 电压激活的分子基础尚不清楚。在这里，我们报告了海胆 SLC9C1 在去污剂和纳米盘中的冷冻电子显微镜 (cryo-EM) 结构。我们表明，电压感应结构域位于一种不寻常的构象中，夹在 SLC9C1 同源二聚体的每一侧。S4 段非常长，长 90Å，将电压感应结构域连接到细胞质环核苷酸结合结构域。S4 段处于向上的构象——SLC9C1 的非激活状态。一致地，尽管负电荷腔可用于 Na 与 SLC9C1 的离子转运结构域结合，但与 S4 相连的细胞内螺旋限制了它们的运动。基于 cAMP 存在时 SLC9C1 的 cryo-EM 结构的差异，我们提出，在超极化时，S4 段向下移动，消除这种限制，使 Na/H 交换成为可能。

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