Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH.

Cryo-electron microscopy reveals NHE6 as a homodimer with lipid-dependent regulation, crucial for endosomal pH control, with structures at 2.2–3.3 Å resolution.

• Why it matters: Understanding NHE6's structure and regulation is vital because mutations cause Christianson syndrome, yet its functional mechanisms remain unclear, limiting therapeutic insights.
• What they did: Researchers determined four high-resolution structures of rat NHE6, identified lipid-binding sites for PI3P and PI(4,5)P2, and used electrophysiology to show ion transport and lipid effects on stability and activity.
• The result: Findings suggest lipid interactions regulate NHE6 activity, with PI3P enhancing function in endosomes and PI(4,5)P2 stabilizing an auto-inhibited state at the plasma membrane, illuminating its role in cellular pH regulation.