2.A.58 The Phosphate:Na+ Symporter (PNaS) Family
The PNaS family includes several functionally characterized, sodium-dependent, inorganic phosphate (Pi) transporter (NPT2 or NptA) proteins from mammals. Other animals, including fish and the worm, C. elegans, possess functionally uncharacterized homologues. One closely related bacterial protein, NptA of Vibrio cholerae, resembles the animal proteins (34% identity; 51% similarity to many mammalian Npt2 symporters), but it has close homologues in many bacterial phyla.There are two subfamilies; one includes eukaryotic and prokaryotic proteins, and the other, only bacterial homologues. The bacterial proteins are found in many bacteria including E. coli (543 aas; TC# 2.A.58.2.1; 9 putative TMSs) and Bacillus subtilis (310 aas; TC# 2.A.58.2.5; 8 putative TMSs). The bacterial homologue, NptA of V. cholerae has 10 putative TMSs. The well-characterized mammalian proteins are found in renal (IIa isoform) and intestinal (IIb isoform) brush border membranes and are about 640 amino acyl residues long with 8-12 putative TMSs. The N- and C-termini are in the cytoplasm, and a large hydrophilic loop is localized between TMSs 3 and 4. While IIa isoforms are pH-dependent, IIb isoforms are pH-independent (de la Horra et al., 2000). Members of this family have been reported to have the CNT2 fold (Ferrada and Superti-Furga 2022).
Mammalian porters of the PNaS family may catalyze cotransport of 3 Na+ with 1 inorganic phosphate. In response to parathyroid hormone and dietary inorganic phosphate, the renal cotransporter is rapidly inserted into and retrieved from the renal brush border membrane in a fashion similar to that by which the glucose transporter (Glut4) (TC# 2.A.1.1) is regulated by insulin, and aquaporins 1 and 2 (TC# 1.A.8.1) are regulated by vasopressin (Levi et al., 1999). The renal type IIa PNaS member is a functional monomer (Kohler et al., 2001), but it interacts with PDZ proteins which probably mediate apical sorting, parathyroid hormone-controlled endocytosis and/or lysosomal sorting of internalized transporter (Gisler et al., 2001).
A single organism may have multiple paralogues of the PNaS family. All of these proteins exhibit an internal repeat that probably arose by a tandem intragenic duplication event. Their properties and mechanisms of action have been reviewed (Forster 2019).
The transport reaction catalyzed by the mammalian proteins is:
Pi (out) + 3 Na+ (out) ⇌ Pi (in) + 3 Na+ (in).