SLC17: a functionally diverse family of organic anion transporters

Abstract

Molecular studies have determined that the SLC17 transporters, a family of nine proteins initially implicated in phosphate transport, mediate the transport of organic anions. While their role in phosphate transport remains uncertain, it is now clear that the transport of organic anions facilitated by this family of proteins is involved in diverse processes ranging from the vesicular storage of the neurotransmitters, to urate metabolism, to the degradation and metabolism of glycoproteins.

Figure 1. Phylogenetic tree with human isoforms of the SLC17 family

Computer-based phylogenetic analysis of the identified members of the SLC17 family of proteins illustrates four distinct branches. There is a high degree of similarity among the VGLUT sequences (74–82% identity) and sialin and VNUT are more closely related to the VGLUTs (38% identity and 57% similarity over 489 amino acids for VGLUT1 (SLC17A7) and sialin (SLC17A5) and 27% identity and 47% similarity over 436 amino acids for VGLUT1 and VNUT (SLC17A9)) than to the type I phosphate transporters (37% identity and 54% similarity between over 467 amino acids for NPT1 (SLC17A1) and sialin and 24% identity and 43% similarity over 397 amino acids for VNUT and NPT1= 170/397 (43%)). The tree was generated using the AllAll program of the Computational Biochemistry Research Group, Swiss Federal Institute of Technology, Zurich, Switzerland (http://www.cbrg.ethz.ch/services/AllAll) using protein translations of the mRNA sequences listed under the following accession numbers: NM_005074.3, NM_003052.4, NM_001098486.1, NM_006632.3, NM_005495.2, NM_012434.4, NM_020346.2, NM_020309.3, NM_139319.2, NM_001145288.1, and NM_022082.3.

Figure 2. Conserved residues in the SLC17 family of proteins

A) PredictProtein-derived topology model for human sialin sequence with manual adjustments. The circled residues are conserved among all nine SLC17 proteins across vertebrate species in which the proteins have been identified. B) Inward (cytoplasmic)-facing and outward (lumenal/extracellular)-facing models of sialin based on structures of the bacterial MFS transporters GlpT and FucP, respectively. Structures are sequentially color coded from blue at the N-terminus to red at the C-terminus. Sequence-structure alignments were provided by Lei Shi (Weill Cornell Medical College) and derived with PROMALS3D. Images were generated in MacPymol2 (PyMOL Molecular Graphics System, Version 1.3 Schrödinger, LLC).

Figure 3. Physiology of the SLC17 transporters

A) The type I phosphate transporters NPT1 and NPT3 have been implicated in secretion of organic ions including urate and drugs in the renal tubules for secretion. B) Sialin mediates the H+ coupled efflux of sialic acid from the acidic lysosome. The degradation of oligosaccharides and glycoproteins leads to the generation of free sialic acid (SA) in lysosomes. The free sialic acid released into the cytoplasm for further metabolism or incorporation into newly synthesized glycoproteins and glycolipids in the golgi. C) The VGLUTs and VNUT both concentrate neurotransmitters (glutamate for VGLUTs and purines including ATP for VNUT) into neurosecretory vesicles for regulated release. This activity requires the electrochemical gradient generated by a H+-ATPase on the secretory vesicles. Both glutamate and ATP are present in all cells, but their release through exocytosis requires active transport into secretory vesicles by these transporters. The VGLUTs and VNUT are thus the defining molecular markers for glutamatergic and purinergic neurons. D) Proposed transport mechanisms for SLC17 transporters. The best characterized transport mechanism among in the SLC17 family is symport of acidic sugars and H⁺ by sialin. Electrogenic uniport of substrate with allosteric modulation by Cl- has been proposed for NPT1, the VGLUTs and VNUT. Other transport mechanisms that have been proposed include exchange of glutamate and H⁺ for the VGLUTs, an inorganic anion channel activity for NPT1 and VGLUT1, and Na⁺ - PO4⁻⁻ cotransport for NPT1, VGLUT1, and VGLUT2.