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Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger
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Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger
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Journal Article
Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger
2023
Overview
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.
Upon hyperpolarization, the S4 voltage-sensing segment of sea urchin SLC9C1 moves down, removing inhibition caused by an intracellular helix and enabling Na
+
/H
+
exchange, leading to pH-dependent activation of sAC and sperm chemotaxis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 13/109
/ 82/16
/ 82/80
/ 82/83
/ 9/10
/ Adenylyl Cyclases - metabolism
/ Animals
/ Flagella
/ Humanities and Social Sciences
/ Hydrogen
/ Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - chemistry
/ Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism
/ Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - ultrastructure
/ Male
/ Motility
/ Science
/ Sea Urchins - ultrastructure
/ Segments
/ Sodium channels (voltage-gated)
/ Sodium-Hydrogen Exchangers - chemistry
/ Sodium-Hydrogen Exchangers - metabolism
/ Sodium-Hydrogen Exchangers - ultrastructure
/ Sperm
/ Spermatozoa - ultrastructure
/ Symmetry
