8OTW

Cryo-EM structure of Strongylocentrotus purpuratus SLC9C1 in presence of cAMP

Summary for 8OTW

• Entry DOI: 10.2210/pdb8otw/pdb
• EMDB information: 17185
• Descriptor: Sperm-specific sodium proton exchanger, 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE (2 entities in total)
• Functional Keywords: vsd, cnbd, transporter, voltage sensor, exchanger, sperm motility, camp binding, transport protein
• Biological source: Strongylocentrotus purpuratus (purple sea urchin)
• Total number of polymer chains: 2
• Total formula weight: 296578.78

Authors

Yeo, H.,Mehta, V.,Gulati, A.,Drew, D. (deposition date: 2023-04-21, release date: 2023-11-01, Last modification date: 2023-11-22)

Primary citation

Yeo, H.,Mehta, V.,Gulati, A.,Drew, D.
Structure and electromechanical coupling of a voltage-gated Na + /H + exchanger.
Nature, 623:193-201, 2023

PubMed 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.

PubMed: 37880360
DOI: 10.1038/s41586-023-06518-2

Experimental method

ELECTRON MICROSCOPY (3.68 Å)