여현구 (Stockholm University)

한빛사논문

조회664

Stockholm University

CV File 747 kb

Nature, Nov 2023, 623 (7985) | https://doi.org/10.1038/s41586-023-06518-2 Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger

Hyunku Yeo^1,2, Ved Mehta^1,2, Ashutosh Gulati^1,2& David Drew¹

¹Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.

²These authors contributed equally: Hyunku Yeo, Ved Mehta, Ashutosh Gulati.

Corresponding author : Correspondence to David Drew.

Abstract

Voltage-sensing domains control the activation of voltage-gated ion channels, with a few exceptions ¹. One such exception is the sperm-specific Na ⁺/H ⁺ exchanger SLC9C1, which is the only known transporter to be regulated by voltage-sensing domains ^2-5. After hyperpolarization of sperm flagella, SLC9C1 becomes active, causing pH alkalinization and CatSper Ca ²⁺ channel activation, which drives chemotaxis ^2,6. SLC9C1 activation is further regulated by cAMP ^2,7, which is produced by soluble adenyl cyclase (sAC). SLC9C1 is therefore an essential component of the pH-sAC-cAMP signalling pathway in metazoa ^8,9, required for sperm motility and fertilization ⁴. 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.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-13)
연구진국외 연구진
분야 생명과학 > 구조생물 및 생물물리학

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