2.A.36.2.2
The electroneutral Na⁺/Li⁺:H⁺ antiporter, Nha2. Catalyzes Na⁺:Li⁺ antiport; contributes to salt homeostasis. It correlates with heritable hypertension (Xiang et al., 2007) and is critical for insulin secretion (Deisl et al. 2013). Like electrogenic Na⁺/H⁺ exchangers, it has two conserved aspartyl residues in the Na⁺ binding site but seems to be electroneutral (Uzdavinys et al. 2017). The structure, mechanism and lipid-mediated remodeling of the mammalian Na⁺/H⁺ exchanger NHA2, linked to the pathogenesis of diabetes mellitus, have been described (Matsuoka et al. 2022). NHA2 consists of 14 TMSs, rather than the 13 previously observed in mammalian NHEs and related bacterial antiporters. 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. Possibly the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity (Matsuoka et al. 2022).  There are allosteric links between the hydrophilic N-terminus and the transmembrane core of human Na⁺ /H⁺ antiporter NHA2 (Velázquez et al. 2022).