瑞典斯德哥尔摩大学David Drew研究团队揭示电压门控Na+/H+交换器的结构与机电耦合。相关论文于2023年10月25日在线发表于国际学术期刊《自然》。

研究人员表示，电压感应结构域控制着电压门控离子通道的激活，但也有少数例外。精子特异性Na⁺/H⁺交换蛋白SLC9C1就是这样一个例外，它是唯一已知的受电压感应结构域调控的转运体。精子鞭毛超极化后，SLC9C1开始活跃，导致pH碱化和CatSper Ca²⁺通道激活，从而驱动趋化作用。SLC9C1的激活还受可溶性腺苷酸环化酶（sAC）产生的cAMP的进一步调节。因此，SLC9C1是后生生物pH-sAC-cAMP信号通路的重要组成部分，并是精子运动和受精所需的。尽管SLC9C1非常重要，但其电压激活的分子基础尚不清楚。

研究人员报告了海胆SLC9C1在去垢剂和纳米盘中的冷冻电子显微镜（cryo-EM）结构。研究人员发现，电压感应结构域以一种不寻常的构型位于SLC9C1同源二聚体的两侧。S4区段很长，长达90 Å，连接着电压感应结构域和细胞质环状核苷酸结合结构域。S4段处于向上构型，即SLC9C1的非活性状态。一致的是，虽然Na⁺可以通过带负电荷的空腔与SLC9C1的离子转运结构域结合，但与S4相连的胞内螺旋限制了它们的移动。根据SLC9C1的cryo-EM结构在cAMP存在下的差异，研究人员提出，在超极化时，S4段向下移动，消除了这一限制，从而实现了Na⁺/H⁺交换。

附：英文原文

Title: Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger

Author: Yeo, Hyunku, Mehta, Ved, Gulati, Ashutosh, Drew, David

Issue&Volume: 2023-10-25

Abstract: Voltage-sensing domains control the activation of voltage-gated ion channels, with a few exceptions1. One such exception is the sperm-specific Na+/H+ exchanger SLC9C1, which is the only known transporter to be regulated by voltage-sensing domains2,3,4,5. After hyperpolarization of sperm flagella, SLC9C1 becomes active, causing pH alkalinization and CatSper Ca2+ channel activation, which drives chemotaxis2,6. SLC9C1 activation is further regulated by cAMP2,7, which is produced by soluble adenyl cyclase (sAC). SLC9C1 is therefore an essential component of the pH–sAC–cAMP signalling pathway in metazoa8,9, required for sperm motility and fertilization4. 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 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.

DOI: 10.1038/s41586-023-06518-2

Source: https://www.nature.com/articles/s41586-023-06518-2