8PS0

Cryo-EM structure of Sodium proton exchanger NhaA with bound cardiolipin

Summary for 8PS0

• Entry DOI: 10.2210/pdb8ps0/pdb
• EMDB information: 17841
• Descriptor: Na(+)/H(+) antiporter NhaA, CARDIOLIPIN (2 entities in total)
• Functional Keywords: sodium proton exchanger, cardiolipin, nhaa, transport protein
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 89000.97

Authors

Gulati, A.,Meier, P.,Kokane, S.,Drew, D. (deposition date: 2023-07-13, release date: 2024-02-21, Last modification date: 2025-09-03)

Primary citation

Kokane, S.,Gulati, A.,Meier, P.F.,Matsuoka, R.,Pipatpolkai, T.,Albano, G.,Ho, T.M.,Delemotte, L.,Fuster, D.,Drew, D.
PIP 2 -mediated oligomerization of the endosomal sodium/proton exchanger NHE9.
Nat Commun, 16:3055-3055, 2025

PubMed Abstract: The strict exchange of Na for H ions across cell membranes is a reaction carried out in almost every cell. Na/H exchangers that perform this task are physiological homodimers, and whilst the ion transporting domain is highly conserved, their dimerization differs. The Na/H exchanger NhaA from Escherichia coli has a weak dimerization interface mediated by a β-hairpin domain and with dimer retention dependent on cardiolipin. Similarly, organellar Na/H exchangers NHE6, NHE7 and NHE9 also contain β-hairpin domains and recent analysis of Equus caballus NHE9 indicated PIP lipids could bind at the dimer interface. However, structural validation of the predicted lipid-mediated oligomerization has been lacking. Here, we report cryo-EM structures of E. coli NhaA and E. caballus NHE9 in complex with cardiolipin and phosphatidylinositol-3,5-bisphosphate PI(3,5)P lipids binding at their respective dimer interfaces. We further show how the endosomal specific PI(3,5)P lipid stabilizes the NHE9 homodimer and enhances transport activity. Indeed, we show that NHE9 is active in endosomes, but not at the plasma membrane where the PI(3,5)P lipid is absent. Thus, specific lipids can regulate Na/H exchange activity by stabilizing dimerization in response to either cell specific cues or upon trafficking to their correct membrane location.

PubMed: 40155618
DOI: 10.1038/s41467-025-58247-x

Experimental method

ELECTRON MICROSCOPY (3.37 Å)