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2.A.36 The Monovalent Cation:Proton Antiporter-1 (CPA1) Family

The CPA1 family is a large family of proteins derived from Gram-positive and Gram-negative bacteria, blue-green bacteria, archaea and eukaryotes including yeast, plants and animals. Transporters from eukaryotes have been functionally characterized, and all of these catalyze Na+:H+ exchange. Their primary physiological functions may be in (1) cytoplasmic pH regulation, extruding the H+ generated during metabolism, and (2) salt tolerance (in plants), due to Na+ uptake into vacuoles. Bacterial homologues are also Na+:H+ antiporters, but some also catalyze Li+:H+ antiport or Ca2+:H+ antiport under some conditions (Waditee et al., 2001).  The pathophylsiology of human members of this family have been reviewed (Padan and Landau 2016). Most prokaryotic Na+/H+ exchangers belong to the Cation/Proton Antiporter (CPA) superfamily, the Ion Transport (IT) superfamily, or the Na+-translocating Mrp transporter superfamily (Patiño-Ruiz et al. 2022). Transport mechanisms for Na+/H+ exchangers that explain their highly pH-regulated activity profiles have been considered (Patiño-Ruiz et al. 2022). Dwivedi and Mahendiran 2022 describe the interplay in the structure-function of membrane transporter proteins that may be implemented to explore the plethora of biological events such as conformation, folding, ion binding and translocation.

The phylogenetic tree for the CPA1 family shows three principal clusters. The first cluster includes proteins derived exclusively from animals, and all of the functionally characterized members of the family belong to this cluster. Of the two remaining clusters, one includes all bacterial homologues while the other includes one from Arabidopsis thaliana, one from Homo sapiens and two from yeast (S. cerevisiae and S. pombe). Several organisms possess multiple paralogues; for example seven paralogues are found in C. elegans, and five are known for humans. Most of these paralogues are very similar in sequence, and they belong to the animal specific cluster.

Using the mammalian NHE1 (2.A.36.1.1), it has been found that TMSs 4 and 9 as well as the extracellular loop between TMSs 3 and 4 are important for drug (amiloride- and benzoyl guanidinium-based derivatives) sensitivities. Mutations in these regions also affect transport activities. M4 and M9 therefore contain critical sites for both drug and cation recognition. Cation/proton antiporters (CPAs) regulate cells' salt concentrations and internal pH. Their malfunction is associated with a range of human pathologies, yet only a handful of CPA-targeting therapeutics are presently in clinical studies. Masrati et al. 2023 discussed how recently published mammalian protein structures and emerging computational technologies may help to bridge this gap.

Daxx, a death domain-associated protein, (O35613) interacts with sodium hydrogen exchanger isoform 1 (NHE1). During ischemic stress, Daxx translocates from the nucleus to the cytoplasm, where it colocalizes with NHE1. Daxx binds to the ezrin/radixin/moesin (ERM)-interacting domain of NHE1, in competition with ezrin. Ischemic insult may trigger the nucleo-cytoplasmic translocation of Daxx, following which cytoplasmic Daxx stimulates the NHE1 transporter activity and suppresses activation of the NHE1-ezrin-Akt-1 pathway (Jung et al., 2007).

One homologue, Nhe (TC #2.A.36.1.4), is a chloride-dependent Na+:H+ antiporter in which residues 1-375 of the 438 aas are identical to Nhe-1 (TC #2.A.36.1.1). The C-terminal 63 residues are unique (Sangan et al., 2002). It is found in the apical membranes of crypt cells of the rat distal colon. This protein was reported to exhibit 6 putative TMSs and is encoded by a 2.5 kb mRNA present in many tissues (Sangan et al., 2002). However, the WHAT program predicts 10 TMSs. nhe transfected fibroblasts exhibit Cl--dependent Na+-dependent intracellular pH recovery to an acid load that was blocked by 5-ethylisopropylamiloride and 5'-nitro-2-(3-phenylpropylamino)benzoate (a Cl- channel blocker).

Numerous members of the CPA1 family have been sequenced, and these proteins vary substantially in size. The bacterial proteins have 527-549 amino acyl residues while eukaryotic proteins are generally larger, varying in size from 541-894 residues. They exhibit 10-12 putative transmembrane α-helical spanners (TMSs). A proposed topological model (Wakabayashi et al., 2000) suggests that in addition to 12 TMSs, a region between TMSs 9 and 10 dips into the membrane to line the pore. However, one homologue, Nhx1 of S. cerevisiae, has an extracellular glycosylated C-terminus (Wells and Rao, 2001).

A gene encoding a Na+/H+ antiporter was cloned from the chromosome of Halobacillus dabanensis strain D-8(T) by functional complementation. Its presence enabled the antiporter-deficient E. coli strain KNabc to survive in the presence of 0.2 M NaCl or 5 mM LiCl (Yang et al. 2006). The gene was sequenced and designated as nhaH (2.A.36.6.7). NhaH has 403 residues and is 54% identical and 76% similar to the NhaG Na+/H+ antiporter of Bacillus subtilis (TC# 2.A.36.6.2). The hydropathy profile was characteristic of a membrane protein with 12 putative transmembrane domains. Everted membrane vesicles prepared from E. coli cells carrying nhaH exhibited Na+/H+ as well as Li+/H+ antiporter activity, which was pH-dependent with highest activities at pH 8.5-9.0 and at pH 8.5, respectively. nhaH confers upon E. coli KNabc cells the ability to grow under alkaline conditions (Yang et al., 2006). 

Na+, K+ and pH homeostasis are controlled by the monovalent cation proton antiporter (CPA) superfamily. Kong et al. 2021 identified 35 ZmCPAs in maize comprising 13 Na+/H+ exchangers (ZmNHXs), 16 cation/H+ exchanger (ZmCHXs), and 6 K+ efflux antiporters (ZmKEAs). Most of them were localized to the plasma membrane or tonoplast. ZmCHXs were highly expressed in anthers, while ZmNHXs and ZmKEAs showed high expression in various tissues. ZmNHX5 and ZmKEA2 were up-regulated in maize seedlings under both NaCl and KCl stresses. Yeast complementation experiments revealed the roles of ZmNHX5, ZmKEA2 in NaCl tolerance (Kong et al. 2021).

Membrane ion channels and Na+-Li+/H+ exchangers (NHEs) fractionate Li isotopes (Poet et al. 2023). This systematic 6Li enrichment is driven by the membrane potential for channels, and by intracellular pH for NHEs, where it displays cooperativity, a hallmark of dimeric transport, evidencing that transport proteins discriminate between isotopes differing by one neutron.

The generalized transport reaction catalyzed by functionally characterized members of the CPA1 family is:

Na+ (out) + H+ (in) ⇌ Na+ (in) + H+ (out)

This family belongs to the: CPA Superfamily.

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