Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH
The sodium-proton exchanger NHE6 localises to endosomal membranes and mutations in the protein are known to cause the X-linked neurological disorder Christianson syndrome. Here the authors report four cryo-EM structures
Sodium-proton exchangers (NHEs) play a crucial role in regulating intracellular pH, sodium levels, and cell volume in all cells. In humans, there are nine different NHE transporters (SLC9A1-9), which vary in tissue distribution, kinetics, and regulation. The specific function of NHE6, however, remains unclear due to the lack of structural information. This study presents four cryo-electron microscopy structures of rat NHE6 at resolutions ranging from 2.2 to 3.3 Å, revealing its homodimeric structure, ion binding sites, and lipid-mediated interactions. The authors identify a unique lipid-binding site between the protomers that accommodates endosomal-specific phosphatidylinositol 3-phosphate (PI3P) lipid. This interaction enhances NHE6 stability and activity, whereas phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipid interacts with the C-terminal domain to stabilize an auto-inhibited state. Furthermore, the study demonstrates that NHE6 is non-functional when mislocalized to the plasma membrane, where PI(4,5)P2 is primarily located. The authors propose that lipid-dependent regulation has evolved to shut down NHE6 activity during endosomal recycling at the plasma membrane.