The SLC26 gene family of anion transporters and channels

Abstract

The phylogenetically ancient SLC26 gene family encodes multifunctional anion exchangers and anion channels transporting a broad range of substrates, including Cl(-), HCO3(-), sulfate, oxalate, I(-), and formate. SLC26 polypeptides are characterized by N-terminal cytoplasmic domains, 10-14 hydrophobic transmembrane spans, and C-terminal cytoplasmic STAS domains, and appear to be homo-oligomeric. SLC26-related SulP proteins of marine bacteria likely transport HCO3(-) as part of oceanic carbon fixation. SulP genes present in antibiotic operons may provide sulfate for antibiotic biosynthetic pathways. SLC26-related Sultr proteins transport sulfate in unicellular eukaryotes and in plants. Mutations in three human SLC26 genes are associated with congenital or early onset Mendelian diseases: chondrodysplasias for SLC26A2, chloride diarrhea for SLC26A3, and deafness with enlargement of the vestibular aqueduct for SLC26A4. Additional disease phenotypes evident only in mouse knockout models include oxalate urolithiasis for Slc26a6 and Slc26a1, non-syndromic deafness for Slc26a5, gastric hypochlorhydria for Slc26a7 and Slc26a9, distal renal tubular acidosis for Slc26a7, and male infertility for Slc26a8. STAS domains are required for cell surface expression of SLC26 proteins, and contribute to regulation of the cystic fibrosis transmembrane regulator in complex, cell- and tissue-specific ways. The protein interactomes of SLC26 polypeptides are under active investigation.

Figure 1

Phylogenetic relationship of human SLC26 polypeptides generated with Jalview (http://www.jalview.org) using NCBI protein sequences listed in Table 1. Distance matrices were calculated from % sequence identity using average distance algorithm (UPGMA). Average relative distances are shown in bold italics. Sequence identities are shown without italics.

Figure 2

Structural topology model of SLC26 polypeptides showing the short cytoplasmic N-terminal region followed by a transmembrane domain with 12 putative membrane-spanning α-helices, and the C-terminal cytoplasmic region, largely comprising the STAS domain. The STAS domain shown is the backbone structure of the human pendrin STAS domain encompassing aa 515–734 (excluding the intervening sequence (IVS) region of aa 566–653 between helix α1 and strand β3), as modeled with PyMOL from the X-ray crystal structure of rat SLC26A5/prestin (PDB ID 3LLO).

Figure 3

A. Schematic diagram of enterocyte or proximal tubular SO₄²⁻ absorption and secretion involving apical SLC26A2 and SLC13A1, and basolateral SLC26A1. B. Schematic diagram of enterocyte or proximal tubular oxalate secretion involving basolateral SLC26A1 and apical SLC26A6.

Figure 4

A. Schematic diagram of enterocyte NaCl absorption mediated by coupled function of SLC26A3 and NHE3. The basolateral Cl⁻ exit pathways may be multiple. B. Schematic of enterocyte or pancreatic duct cell secretion of HCO₃⁻ and Cl⁻ via coordinated action of apical CFTR, SLC26A6, and SLC26A3. C. Schematic of enterocyte apical SLC26A6 facilitating H⁺-peptide cotransport by apical HPEPT, and being faciliated by apical GLUT5-mediated fructose transport. Carbonic anhydrases are required for activities in all panels (not shown).

Figure 5

A. Schematic of a renal cortical collecting duct Type B intercalated cell absorbing NaCl via coupled apical function of SLC26A4 and SLC4A8 (with contribution from basolateral vH⁺-ATPase), and secreting HCO₃⁻ via apical SLC26A4 and basolateral vH⁺-ATPase, with possible contribution of basolateral SLC26A11 (which also facilitates or may itself mediate anion conductance). B. Schematic of a renal collecting duct Type A intercalated cell secreting acid via the apical vH⁺-ATPase and basolateral SLC4A1 and SLC26A7, with possible contribution of apical SLC26A11. Carbonic anhydrases are required for activities in both panels (not shown).

Figure 6

A. Schematic of a thyrocyte secreting I⁻ into the thyroid follicle by coordinated action of basolateral SLC5A5 (Na⁺/I⁻ symporter) and apical SLC26A4. B. Airway epithelial cell secreting anions by activity of apical SLC26A4 and SLC26A9. (Apical CFTR and Ca²⁺-activated Cl⁻ channels not shown). C. Gastric parietal cell secreting H⁺ by combined basolateral activities of SLC26A7, SLC4A2, and NKCC1, and apical activity of H+,K+-ATPase, with contribution from SLC26A9 (predominantly expressed in surface mucosal cells). Carbonic anhydrases are required for activities in panels B and C (not shown).