Quaternary structure and apical membrane sorting of the mammalian NaSi-1 sulfate transporter in renal cell lines

Regeer, Ralf R.; Nicke, Annette; Markovich, Daniel

doi:10.1016/j.biocel.2007.06.015

Cited by 12 publications

(7 citation statements)

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“…Significant cis-inhibition for NaS1-induced sulfate transport was observed with thiosulfate, selenate, tungstate and molybdate and with succinate and citrate (Lee et al 2000a). The NaS1 protein is localized to the BBM (Regeer et al 2007) of renal proximal tubular cells (Lotscher et al 1996;Markovich et al 1999a;Regeer et al 2007) and encodes a protein of 595 amino acids (&66 kDa) with 13 putative transmembrane domains (Beck and Markovich 2000;Lee et al 2000a). The human NaS1 gene (SLC13A1) consists of 15 exons (spanning[83 kb) localized on human chromosome 7q31-7q32 (Lee et al 2000a).…”

Section: Cloning and Functional Characterization Of Renal Sulfate Tramentioning

confidence: 99%

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Markovich

2011

Arch. Immunol. Ther. Exp.

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This review summarizes the physiological roles of the renal sulfate transporters NaS1 (Slc13a1) and Sat1 (Slc26a1). NaS1 and Sat1 encode renal anion transporters that mediate proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia. Sat1 null mice also exhibit hyperoxalemia, hyperoxaluria and calcium oxalate urolithiasis. Dysregulation of NaS1 and Sat1 leads to hypersulfaturia, hyposulfatemia and liver damage. Loss of Sat1 leads additionally to hyperoxaluria with hyperoxalemia, nephrocalcinosis and calcium oxalate urolithiasis. These data indicate that the renal anion transporters NaS1 and Sat1 are essential for sulfate and oxalate homeostasis, respectively.

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Section: Cloning and Functional Characterization Of Renal Sulfate Tramentioning

confidence: 99%

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Markovich

2011

Arch. Immunol. Ther. Exp.

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“…Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed: 110 E. Warren Ave., Detroit, MI 48201. many membrane transporters (15)(16)(17)(18). For major facilitator superfamily proteins, both monomeric (e.g.…”

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confidence: 99%

Oligomeric Structure of the Human Reduced Folate Carrier

Hou

Matherly

2009

Journal of Biological Chemistry

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The ubiquitously expressed reduced folate carrier (RFC) is the major transport system for folate cofactors in mammalian cells and tissues. Previous considerations of RFC structure and mechanism were based on the notion that RFC monomers were sufficient to mediate transport of folate and antifolate substrates. The present study examines the possibility that human RFC (hRFC) exists as higher order homo-oligomers. By chemical cross-linking, transiently expressed hRFC in hRFC-null HeLa (R5) cells with the homobifunctional cross-linker 1,3-propanediyl bis-methanethiosulfonate and Western blotting, hRFC species with molecular masses of hRFC homo-oligomers were identified. Hemagglutinin-and Myc epitope-tagged hRFC proteins expressed in R5 cells were co-immunoprecipitated from both membrane particulate and surface-enriched membrane fractions, indicating that oligomeric hRFC is expressed at the cell surface. By co-expression of wild type and inactive mutant S138C hRFCs, combined with surface biotinylation and confocal microscopy, a dominant-negative phenotype was demonstrated involving greatly decreased cell surface expression of both mutant and wild type carrier caused by impaired intracellular trafficking. For another hRFC mutant (R373A), expression of oligomeric wild type-mutant hRFC was accompanied by a significant and disproportionate loss of wild type activity unrelated to the level of surface carrier. Collectively, our results demonstrate the existence of hRFC homo-oligomers. They also establish the likely importance of these higher order hRFC structures to intracellular trafficking and carrier function.Folates are members of the B class of vitamins that are required for the synthesis of nucleotide precursors, serine, and methionine in one-carbon transfer reactions (1). Because mammals cannot synthesize folates de novo, cellular uptake of these derivatives is essential for cell growth and tissue regeneration (2, 3). Folates are hydrophilic anionic molecules that do not cross biological membranes by diffusion alone, so it is not surprising that sophisticated membrane transport systems have evolved to facilitate their accumulation by mammalian cells.The ubiquitously expressed reduced folate carrier (RFC) 2 is widely considered to be the major transport system for folate co-factors in mammalian cells and tissues (3, 4). RFC plays a generalized role in folate transport and provides specialized tissue functions such as transport across the basolateral membrane of renal proximal tubules (5), transplacental transport of folates (6), and folate transport across the blood-brain barrier (7), although the contribution of RFC to intestinal absorption of folates remains controversial (8, 9). Loss of RFC expression or function portends potentially profound physiologic and developmental consequences associated with folate deficiency (10). RFC is also a major transporter of antifolate drugs used for cancer chemotherapy such as methotrexate (Mtx), pemetrexed, and raltitrexed (4). Loss of RFC expression or synthesis of mutant RFC...

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“…The presence of a highly conserved protein kinase C phosphorylation motif (close to TMD IX) found in all fish and mammalian NaS1 sequences (Thr 423 in human and rat, Thr 422 in mouse, Thr 445 in Japanese eel, and Thr 412 in zebrafish) and a large protein kinase C phosphorylation motifrich area (in the intracellular loop between TMD IV and V) would merit further analysis. The function of mammalian NaS1 proteins has already been investigated by single amino acid substitution analysis to define relevant structural/functional motifs or domains (16,17,19,28). Using comparative analysis, we have confirmed identity or conservative substitutions along the vertebrate series of all those amino acids centered around Ser 260 in human NaS1 (namely, Thr 257 -Gly 258 -Thr 259 -Ser 260 -Thr 261 -Asn 262 -Leu 263 ), for which mutational analysis has established a significant effect on function (17).…”

Section: Discussionmentioning

confidence: 99%

Functional and structural characterization of the zebrafish Na⁺-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1)

Markovich

Romano

Storelli

et al. 2008

Physiological Genomics

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Sulfate plays an essential role during growth, development and cellular metabolism. In this study, we characterized the function and structure of the zebrafish (Danio rerio) Na+-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1). Zebrafish NaS1 encodes a protein of 583 amino acids with 13 putative transmembrane domains. Expression of zebrafish NaS1 protein in Xenopus oocytes led to Na+-sulfate cotransport, which was significantly inhibited by thiosulfate, selenate, molybdate, and tungstate. Zebrafish NaS1 transport kinetics were: V(max) = 1,731.670 +/- 92.853 pmol sulfate/oocyte.hour and K(m) = 1.414 +/- 0.275 mM for sulfate and V(max) = 307.016 +/- 32.992 pmol sulfate/oocyte x hour, K(m) = 24.582 +/- 4.547 mM and n (Hill coefficient) = 1.624 +/- 0.354 for sodium. Zebrafish NaS1 mRNA is developmentally expressed in embryos from day 1 postfertilization and in the intestine, kidney, brain, and eye of adult zebrafish. The zebrafish NaS1 gene slc13a1 contains 15 exons spanning 8,716 bp. Characterization of the zebrafish NaS1 contributes to a greater understanding of sulfate transporters in a well-defined genetic model and will allow the elucidation of evolutionary and functional relationships among vertebrate sulfate transporters.

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Quaternary structure and apical membrane sorting of the mammalian NaSi-1 sulfate transporter in renal cell lines

Cited by 12 publications

References 49 publications

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Oligomeric Structure of the Human Reduced Folate Carrier

Functional and structural characterization of the zebrafish Na⁺-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1)

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Quaternary structure and apical membrane sorting of the mammalian NaSi-1 sulfate transporter in renal cell lines

Cited by 12 publications

References 49 publications

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Physiological Roles of Mammalian Sulfate Transporters NaS1 and Sat1

Oligomeric Structure of the Human Reduced Folate Carrier

Functional and structural characterization of the zebrafish Na+-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1)

Contact Info

Product

Resources

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Functional and structural characterization of the zebrafish Na⁺-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1)