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Luminal heterodimeric amino acid transporter defective in cystinuria.

ABSTRACT: Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal recessive failure of dibasic amino acid transport (b(0,+) type) across luminal membranes of intestine and kidney cells. Here we identify the permease-like protein b(0,+)AT as the catalytic subunit that associates by a disulfide bond with rBAT to form a hetero-oligomeric b(0,+) amino acid transporter complex. We demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric fusion construct and show its luminal brush border localization in kidney proximal tubule. These biochemical, transport, and localization characteristics as well as the chromosomal localization on 19q support the notion that the b(0,+)AT protein is the product of the gene defective in non-type I cystinuria.

SUBMITTER: Pfeiffer R

PROVIDER: S-EPMC25748 | biostudies-literature | 1999 Dec

REPOSITORIES: biostudies-literature

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Luminal heterodimeric amino acid transporter defective in cystinuria.

Pfeiffer R R Loffing J J Rossier G G Bauch C C Meier C C Eggermann T T Loffing-Cueni D D Kühn L C LC Verrey F F

Molecular biology of the cell 19991201 12

Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal recessive failure of dibasic amino acid transport (b(0,+) type) across luminal membranes of intestine and kidney cells. Here we identify the permease-like protein b(0,+)AT as the catalytic subunit that associates by a disulfide bond with rBAT to form a hetero-oligomeric b(0,+) amino acid transporter complex. We demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric fusion construct and show its lumi ...[more]

PMID: 10588648

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Project description:The cationic amino acid arginine, due to its positive charge, is usually accumulated in the cytosol. Nevertheless, arginine has to be released by a number of cell types, e.g. kidney cells, which supply other organs with this amino acid, or the endothelial cells of the blood-brain barrier which release arginine into the brain. Arginine release in mammalian cells can be mediated by two different transporters, y(+)LAT1 and y(+)LAT2. For insertion into the plasma membrane, these transporters have to be associated with the type-II membrane glycoprotein 4F2hc [Torrents, Estevez, Pineda, Fernandez, Lloberas, Shi, Zorzano and Palacin (1998) J. Biol. Chem. 273, 32437-32445]. The present study elucidates the function and distribution of y(+)LAT2. In contrast to y(+)LAT1, which is expressed mainly in kidney epithelial cells, lung and leucocytes, y(+)LAT2 has a wider tissue distribution, including brain, heart, testis, kidney, small intestine and parotis. When co-expressed with 4F2hc in Xenopus laevis oocytes, y(+)LAT2 mediated uptake of arginine, leucine and glutamine. Arginine uptake was inhibited strongly by lysine, glutamate, leucine, glutamine, methionine and histidine. Mutual inhibition was observed when leucine or glutamine was used as substrate. Inhibition of arginine uptake by neutral amino acids depended on the presence of Na(+), which is a hallmark of y(+)LAT-type transporters. Although arginine transport was inhibited strongly by glutamate, this anionic amino acid was only weakly transported by 4F2hc/y(+)LAT2. Amino acid transport via 4F2hc/y(+)LAT2 followed an antiport mechanism similar to the other members of this new family. Only preloaded arginine could be released in exchange for extracellular amino acids, whereas marginal release of glutamine or leucine was observed under identical conditions. These results indicated that arginine has the highest affinity for the intracellular binding site and that arginine release may be the main physiological function of this transporter.

Dataset Information

Luminal heterodimeric amino acid transporter defective in cystinuria.

Publications

Luminal heterodimeric amino acid transporter defective in cystinuria.

Similar Datasets

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