9S8E
Cryo-EM structure of Rat NHE6 in nanodisc
Summary for 9S8E
| Entry DOI | 10.2210/pdb9s8e/pdb |
| EMDB information | 54661 |
| Descriptor | Sodium/hydrogen exchanger 6 (1 entity in total) |
| Functional Keywords | na+/h+ exchanger, nhe6, transport protein |
| Biological source | Rattus norvegicus (Norway rat) |
| Total number of polymer chains | 2 |
| Total formula weight | 157752.88 |
| Authors | Yeo, H.,Jung, S.,Reichenbach, T.,Kokane, S.,Gulati, A.,Drew, D. (deposition date: 2025-08-05, release date: 2026-07-29, Last modification date: 2026-08-26) |
| Primary citation | 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. Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH. Nat Commun, 17:-, 2026 Cited by PubMed 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)P) 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)P is primarily located. We propose the lipid-dependent regulation has evolved to shut-down NHE6 activity during recycling of endosomes at the plasma membrane. PubMed: 42581050DOI: 10.1038/s41467-026-75877-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.25 Å) |
Structure validation
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