Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH.
Overview
- Department of Biochemistry and Biophysics, Science for Life laboratory, Stockholm University,Stockholm, Sweden
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern,Bern, Switzerland
- Department of Chemistry, Dorothy Crowfoot Hodgkin Building, University of Oxford,Oxford, UK
- Department of Cell and Molecular Biology, Uppsala University,Uppsala, Sweden
Abstract
Sodium-proton exchangers (NHEs) are found in all cells to regulate intracellular pH, sodium levels and cell volume. In humans, there are nine different NHE transporters (SLC9A1-9), which vary in tissue distribution, kinetics and regulation. NHE6 localizes to endosomal membranes and mutations in the protein are known to cause the X-linked neurological disorder Christianson syndrome. Despite its importance, the structural basis of NHE6 function and regulation is unclear. Here we report four cryo-electron microscopy structures of rat NHE6 between 2.2 and 3.3 Å resolution, revealing its homodimeric structure, ion binding and remodelling by lipids. We characterize a lipid-binding site between the protomers that accommodates the endosomal-specific phosphatidylinositol 3-phosphate (PI3P) lipid. Using solid-supported membrane (SSM)-based electrophysiology we demonstrate that NHE6 transports both Na+ and K+ ions and that PI3P enhances NHE6 stability and activity. Furthermore, we identify a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipid, which interacts with the C-terminal domain of NHE6 to stabilize an auto-inhibited state. We further demonstrate that NHE6 is non-functional when mislocalized to the plasma membrane where PI(4,5)P2 is primarily located. We propose the lipid-dependent regulation has evolved to shut-down NHE6 activity during recycling of endosomes at the plasma membrane.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- ebi.ac.uk/
pdbe/ , at EMBL-EBI; found in “Data availability”entry - figshare:31576633, at figshare; found in DataCite
Data availability
Source data are provided with this paper. The coordinates and the maps for cryo-EM structures of rat NHE6 have been deposited in the Electron Microscopy Data Bank (EMD) Protein Data Bank (PDB) with entries: NHE6-nanodisc (EMDB54661 [https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 4 keywords, 13 MeSH terms, 4 funders, 63 references.
Cite
This paper
Jung, S., Yeo, H., Li, H., Kokane, S., Reichenbach, T., Gulati, A., Albano, G., Kirschbaum, C., Ho, T. M., Landreh, M., Abramsson, M., Robinson, C. V., Fuster, D. G., & Drew, D. (2026). Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH. Nature communications, 17(1), 8177. https://
BibTeX
@article{jung2026structu
author = {Jung, Sukkyeong and Yeo, Hyunku and Li, Hang and Kokane, Surabhi and Reichenbach, Tom and Gulati, Ashutosh and Albano, Giuseppe and Kirschbaum, Carla and Ho, Tin Manh and Landreh, Michael and Abramsson, Mia and Robinson, Carol V. and Fuster, Daniel G. and Drew, David},
title = {{Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH}},
journal = {Nature communications},
year = {2026},
month = aug,
volume = {17},
number = {1},
pages = {8177},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {42581050},
pmcid = {PMC13463026}
}
RIS
TY - JOUR
AU - Jung, Sukkyeong
AU - Yeo, Hyunku
AU - Li, Hang
AU - Kokane, Surabhi
AU - Reichenbach, Tom
AU - Gulati, Ashutosh
AU - Albano, Giuseppe
AU - Kirschbaum, Carla
AU - Ho, Tin Manh
AU - Landreh, Michael
AU - Abramsson, Mia
AU - Robinson, Carol V.
AU - Fuster, Daniel G.
AU - Drew, David
TI - Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 8177
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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