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View Proteins belonging to: The Phosphate:Na⁺ Symporter (PNaS) Family

2.A.58 The Phosphate:Na⁺ Symporter (PNaS) Family

The PNaS family includes several functionally characterized, sodium-dependent, inorganic phosphate (P_i) 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:

P_i (out) + 3 Na⁺ (out) ⇌ P_i (in) + 3 Na⁺ (in).

View Proteins belonging to: The Phosphate:Na⁺ Symporter (PNaS) Family

References associated with 2.A.58 family:

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Chen, P., Q. Tang, and C. Wang. (2016). Characterizing and evaluating the expression of the type IIb sodium-dependent phosphate cotransporter (slc34a2) gene and its potential influence on phosphorus utilization efficiency in yellow catfish (Pelteobagrus fulvidraco). Fish Physiol Biochem 42: 51-64. 26298316

Chen, P., Y. Huang, A. Bayir, and C. Wang. (2017). Characterization of the isoforms of type IIb sodium-dependent phosphate cotransporter (Slc34a2) in yellow catfish, Pelteobagrus fulvidraco, and their vitamin D3-regulated expression under low-phosphate conditions. Fish Physiol Biochem 43: 229-244. 27620186

Collins, J.F. and F.K. Ghishan. (1994). Molecular cloning, functional expression, tissue distribution, and in situ hybridization of the renal sodium phosphate (Na⁺/P_i) transporter in the control and hypophosphatemic mouse. FASEB J. 8: 862-868. 8070635

De la Horra, C., N. Hernando, G. Lambert, I. Forster, J. Biber, and H. Murer. (2000). Molecular determinants of pH sensitivity of the type IIa Na/P(i) cotransporter. J. Biol. Chem. 275: 6284-6287. 10692425

Ebert, M., S. Laaß, M. Burghartz, J. Petersen, S. Koßmehl, L. Wöhlbrand, R. Rabus, C. Wittmann, P. Tielen, and D. Jahn. (2013). Transposon mutagenesis identified chromosomal and plasmid genes essential for adaptation of the marine bacterium Dinoroseobacter shibae to anaerobic conditions. J. Bacteriol. 195: 4769-4777. 23974024

Ehnes, C., I.C. Forster, K. Kohler, A. Bacconi, G. Stange, J. Biber, and H. Murer. (2004). Structure-function relations of the first and fourth predicted extracellular linkers of the type IIa Na⁺/Pi cotransporter: I. Cysteine scanning mutagenesis. J Gen Physiol 124: 475-488. 15504898

Fenollar-Ferrer, C., I.C. Forster, M. Patti, T. Knoepfel, A. Werner, and L.R. Forrest. (2015). Identification of the First Sodium Binding Site of the Phosphate Cotransporter NaPi-IIa (SLC34A1). Biophys. J. 108: 2465-2480. 25992725

Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096. 36164651

Forster, I.C. (2019). The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. Pflugers Arch 471: 15-42. 30244375

Ghezzi C., Murer H. and Forster IC. (2009). Substrate interactions of the electroneutral Na+-coupled inorganic phosphate cotransporter (NaPi-IIc). J Physiol. 587(Pt 17):4293-307. 19596895

Gisler, S.M., I. Stagljar, M. Traebert, D. Bacic, J. Biber, and H. Murer. (2001). Interaction of the type IIa Na/P_i cotransporter with PDZ proteins. J. Biol. Chem. 276: 9206-9213. 11099500

Heynemann, S., H. Yu, L. Churilov, G. Rivalland, K. Asadi, R. Mosher, F. Hirsch, C. Rivard, and P. Mitchell. (2021). NaPi2b expression in a large surgical Non-Small Cell Lung Cancer (NSCLC) cohort. Clin Lung Cancer. [Epub: Ahead of Print] 34953676

Jönsson, &.#.1.9.7.;.L.M., O. Hilberg, U. Simonsen, J.H. Christensen, and E. Bendstrup. (2023). New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review. Orphanet J Rare Dis 18: 130. 37259144

Kohler, K., I.C. Forster, G. Lambert, J. Biber, and H. Murer. (2001). The functional unit of the renal type IIa Na⁺/P_i cotransporter is a monomer. J. Biol. Chem 275: 26113-26120. 10859311

Lebens, M., P. Lundquist, L. Söderlund, M. Todorovic, and N.I. Carlin. (2002). The nptA gene of Vibrio cholerae encodes a functional sodium-dependent phosphate cotransporter homologous to the type II cotransporters of eukaryotes. J. Bacteriol. 184: 4466-4474. 12142417

Levi, M., S.A. Kempson, M. Lötscher, J. Biber, and H. Murer. (1996). Molecular regulation of renal phosphate transport. J. Memb. Biol. 154: 1-9. 8881022

Magagnin, S., A. Werner, D. Markovich, V. Sorribas, G. Stange, J. Biber, and H. Murer. (1993). Expression cloning of human and rat renal cortex sodium-phosphorus cotransport. Proc. Natl. Acad. Sci. USA 90: 5979-5983. 8327470

Mamonova, T., Q. Zhang, J.A. Khajeh, Z. Bu, A. Bisello, and P.A. Friedman. (2015). Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1. PLoS One 10: e0129554. 26070212

Motomura, K., R. Hirota, N. Ohnaka, M. Okada, T. Ikeda, T. Morohoshi, H. Ohtake, and A. Kuroda. (2011). Overproduction of YjbB reduces the level of polyphosphate in Escherichia coli: a hypothetical role of YjbB in phosphate export and polyphosphate accumulation. FEMS Microbiol. Lett. 320: 25-32. 21488939

Murer, H., N. Hernando, I. Forster, and J. Biber. (2000). Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol. Rev. 80: 1373-1409. 11015617

Patti, M., C. Fenollar-Ferrer, A. Werner, L.R. Forrest, and I.C. Forster. (2016). Cation Interactions and Membrane Potential Induce Conformational Changes in NaPi-IIb. Biophys. J. 111: 973-988. 27602725

Radanovic, T., S.M. Gisler, J. Biber, and H. Murer. (2006). Topology of the type IIa Na⁺/P(i) cotransporter. J. Membr. Biol. 212: 41-49. 17206517

Saito, A., N.M. Nikolaidis, H. Amlal, Y. Uehara, J.C. Gardner, K. LaSance, L.B. Pitstick, J.P. Bridges, K.A. Wikenheiser-Brokamp, D.W. McGraw, J.C. Woods, Y. Sabbagh, S.C. Schiavi, G. Altinişik, M. Jakopović, Y. Inoue, and F.X. McCormack. (2015). Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med 7: 313ra181. 26560359

Segawa, H., I. Kaneko, A. Takahashi, M. Kuwahata, M. Ito, I. Ohkido, S. Tatsumi, and K. Miyamoto. (2002). Growth-related renal type II NaP_i cotransporter. J. Biol. chem. 277: 19665-19672. 11880379

Stechman, M.J., N.Y. Loh, and R.V. Thakker. (2007). Genetics of hypercalciuric nephrolithiasis: renal stone disease. Ann. N.Y. Acad. Sci. 1116: 461-484. 17872384

Verri, T., D. Markovich, C. Perego, F. Norbis, G. Stange, V. Sorribas, J. Biber, and H. Murer. (1995). Cloning of a rabbit renal Na⁺-P_i cotransporter, which is regulated by dietary phosphate. Am. J. Physiol. 268: F626-F633. 7733319

Yang, Y., J. Wu, X. Yu, Q. Wu, H. Cao, X. Dai, and H. Chen. (2022). SLC34A2 promotes cancer proliferation and cell cycle progression by targeting TMPRSS3 in colorectal cancer. Pathol Res Pract 229: 153706. 34929599

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