![]() Pairwise alignment shows that NHA2 harbors the conserved ion-binding aspartate residues that make up the well-described ‘DD-motif’ 19, 20 found in electrogenic bacterial Na +/H + antiporters, in which the proton-motive force energizes Na + export. Interestingly, NHA2 can also localize to the plasma membrane in specialized cells, such as in the apical membrane of kidney cells, which contains a plasma-membrane-located V-type H +-ATPase 12, 13, or to synaptic-like microvesicles 8, 17. ![]() NHA2 co-localizes with V-type H +-ATPase in all these intracellular organelles 17, 18 wherein cation extrusion is driven by an inwardly directed proton gradient 12. Because of its closer sequence similarity with bacterial antiporters, NHA2 was initially thought to partially localize to mitochondria 16, but it was later established that its predominant localization is in endosomes and lysosomes 17. Furthermore, in vitro and in vivo studies show that NHA2 contributes to β-cell insulin secretion 15. Indeed, NHA2 aids in sodium reabsorption in the kidney 13, 14 and is a critical component of the with-no-lysine kinase 4-sodium-chloride cotransporter (WNK4-NCC) pathway in the regulation of blood pressure 14. Based on tissue expression, genome location and phloretin sensitivity, human NHA2 was proposed to be the candidate gene for the Na +(Li +) countertransport activity associated with the development of essential hypertension and diabetes in humans 9– 12. ![]() By contrast, the mammalian CPA2 clade members NHA1 and NHA2 (SLC9 family 9 members B1 and B2) were more recently identified 4, 8, 9 and share a closer evolutionary relationship to bacterial Na +/H + antiporters 9 (Fig. NHE1 to NHE9 (solute carrier family 9 members A1–9) belong to the CPA1 clade, and are well known for their roles in human physiology, such as Na + reabsorption in the kidney and in acid–base homeostasis 2, 5– 7. In mammals, there are 13 distinct NHE orthologs that belong to the cation:proton antiporter (CPA) superfamily, with differences in tissue and organellar localization, kinetics, regulation and substrate preferences 2– 4. The transmembrane exchange of protons (H +) for either sodium (Na +) or lithium (Li +) ions by Na +/H + exchangers (NHEs) is central to this homeostatic process 1– 3. Intracellular salt, pH and cell volume are tightly regulated for cell survival 1. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na +/H + exchangers (NHEs) and related bacterial antiporters. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. The Na +/H + exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na +/Li + exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans.
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