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Nature
2023 Nov 01;6237985:193-201. doi: 10.1038/s41586-023-06518-2.
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Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger.
Yeo H
,
Mehta V
,
Gulati A
,
Drew D
.
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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 domains2-5. 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 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.
Afonine,
Real-space refinement in PHENIX for cryo-EM and crystallography.
2018, Pubmed
Afonine,
Real-space refinement in PHENIX for cryo-EM and crystallography.
2018,
Pubmed
Ashkenazy,
ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules.
2016,
Pubmed
Bazzone,
SSM-Based Electrophysiology for Transporter Research.
2017,
Pubmed
Bazzone,
Investigation of sugar binding kinetics of the E. coli sugar/H+ symporter XylE using solid-supported membrane-based electrophysiology.
2022,
Pubmed
Boyce,
Simple chained guide trees give high-quality protein multiple sequence alignments.
2014,
Pubmed
Brett,
Evolutionary origins of eukaryotic sodium/proton exchangers.
2005,
Pubmed
Carlson,
CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm.
2003,
Pubmed
Catterall,
The chemical basis for electrical signaling.
2017,
Pubmed
Cavarocchi,
The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility.
2021,
Pubmed
Coincon,
Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters.
2016,
Pubmed
Călinescu,
Electrogenic Cation Binding in the Electroneutral Na+/H+ Antiporter of Pyrococcus abyssi.
2016,
Pubmed
Dong,
Structure and mechanism of the human NHE1-CHP1 complex.
2021,
Pubmed
Dong,
Structural basis of autoinhibition of the human NHE3-CHP1 complex.
2022,
Pubmed
Drew,
Shared Molecular Mechanisms of Membrane Transporters.
2016,
Pubmed
Emsley,
Features and development of Coot.
2010,
Pubmed
Hattori,
A fluorescence-detection size-exclusion chromatography-based thermostability assay for membrane protein precrystallization screening.
2012,
Pubmed
Huang,
Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7.
2022,
Pubmed
Hunte,
Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH.
2005,
Pubmed
Jumper,
Highly accurate protein structure prediction with AlphaFold.
2021,
Pubmed
Krähling,
CRIS-a novel cAMP-binding protein controlling spermiogenesis and the development of flagellar bending.
2013,
Pubmed
Landau,
ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures.
2005,
Pubmed
Lee,
Modulation of the voltage-sensitive Na+/H+ exchange in sea urchin spermatozoa through membrane potential changes induced by the egg peptide speract.
1986,
Pubmed
,
Echinobase
Lee,
A membrane potential-sensitive Na+-H+ exchange system in flagella isolated from sea urchin spermatozoa.
1984,
Pubmed
,
Echinobase
Lee,
A two-domain elevator mechanism for sodium/proton antiport.
2013,
Pubmed
Lee,
Structures of the Human HCN1 Hyperpolarization-Activated Channel.
2017,
Pubmed
Levitan,
Sperm limitation in the sea.
1995,
Pubmed
Lolicato,
Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
2011,
Pubmed
Maes,
Revealing the ligand binding site of NhaA Na+/H+ antiporter and its pH dependence.
2012,
Pubmed
Masrati,
Broad phylogenetic analysis of cation/proton antiporters reveals transport determinants.
2018,
Pubmed
Matsuoka,
Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2.
2022,
Pubmed
Murata,
Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor.
2005,
Pubmed
Nji,
An engineered thermal-shift screen reveals specific lipid preferences of eukaryotic and prokaryotic membrane proteins.
2018,
Pubmed
Nomura,
Structure and mechanism of the mammalian fructose transporter GLUT5.
2015,
Pubmed
Nørholm,
The intracellular distal tail of the Na+/H+ exchanger NHE1 is intrinsically disordered: implications for NHE1 trafficking.
2011,
Pubmed
Paulino,
Structure and transport mechanism of the sodium/proton antiporter MjNhaP1.
2014,
Pubmed
Pedersen,
The SLC9A-C Mammalian Na+/H+ Exchanger Family: Molecules, Mechanisms, and Physiology.
2019,
Pubmed
Perozo,
Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels.
1993,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Punjani,
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination.
2017,
Pubmed
Rimon,
Cardiolipin is an Optimal Phospholipid for the Assembly, Stability, and Proper Functionality of the Dimeric Form of NhaA Na+/H+ Antiporter.
2019,
Pubmed
Romero,
Comparative genomic analysis suggests that the sperm-specific sodium/proton exchanger and soluble adenylyl cyclase are key regulators of CatSper among the Metazoa.
2019,
Pubmed
,
Echinobase
Shen,
Direct measurement of intracellular pH during metabolic derepression of the sea urchin egg.
1978,
Pubmed
,
Echinobase
Shen,
Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins.
2019,
Pubmed
Shin,
Putting the pH into phosphatidic acid signaling.
2011,
Pubmed
Speer,
Molecular mechanisms of sperm motility are conserved in an early-branching metazoan.
2021,
Pubmed
,
Echinobase
Tan,
Structure of the Shaker Kv channel and mechanism of slow C-type inactivation.
2022,
Pubmed
Tao,
A gating charge transfer center in voltage sensors.
2010,
Pubmed
Uzdavinys,
Dissecting the proton transport pathway in electrogenic Na+/H+ antiporters.
2017,
Pubmed
Wakabayashi,
Calmodulin-binding autoinhibitory domain controls "pH-sensing" in the Na+/H+ exchanger NHE1 through sequence-specific interaction.
1997,
Pubmed
Wang,
A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility.
2003,
Pubmed
Wang,
A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC).
2007,
Pubmed
Wennemuth,
Bicarbonate actions on flagellar and Ca2+ -channel responses: initial events in sperm activation.
2003,
Pubmed
Windler,
The solute carrier SLC9C1 is a Na+/H+-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding.
2018,
Pubmed
,
Echinobase
Winkelmann,
Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing.
2022,
Pubmed
Winklemann,
Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9.
2020,
Pubmed
Wöhlert,
Structure and substrate ion binding in the sodium/proton antiporter PaNhaP.
2014,
Pubmed
Xu,
Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.
2019,
Pubmed
Yarov-Yarovoy,
Structural basis for gating charge movement in the voltage sensor of a sodium channel.
2012,
Pubmed
Zhang,
Beyond voltage-gated ion channels: Voltage-operated membrane proteins and cellular processes.
2018,
Pubmed
Zhang,
Structural basis for NaV1.7 inhibition by pore blockers.
2022,
Pubmed
van Kempen,
Fast and accurate protein structure search with Foldseek.
2023,
Pubmed