Normally this protein allows basic, or positively charged amino acids such as histidine, lysine, ornithine, arginine and cysteine to be reabsorbed into the blood from the filtered fluid that will become urine.
If it doesn't work correctly it can cause (apart from cystinuria):
The major transporter for cationic amino acids and cystine in the apical membrane of kidney and intestine is the heteromeric transporter rBAT/b0,+AT (SLC3A1 / SLC7A9).
Heteromeric amino acid transporters (HATs) are composed of a heavy subunit and a light subunit. Two homologous heavy subunits (HSHATs) from the SLC3 family have been cloned and are called rBAT (i.e., related to b0,+ amino acid transport) and 4F2hc [i.e., heavy chain of the surface antigen 4F2hc, also named CD98 or fusion regulatory protein 1 (FRP1)]. Nine light subunits (LSHATs; SLC7 family members from SLC7A5 to SLC7A13) have been identified. Six of them are partners of 4F2hc (LAT1, LAT2, y+LAT1, y+LAT2, asc1, and xCT); one forms a heterodimer with rBAT (b0,+AT); and two (asc2 and AGT-1) seem to interact with as yet unknown heavy subunits. Members SLC7A1–SLC7A4 of family SLC7 correspond to system y+ isoforms (i.e., cationic aminoacid transporters; CATs) and related proteins, which on average show <25% amino acid identity to the light subunits of HATs.
Other transporters involved in cationic amino acid and cystine transport.
Cationic amino acid transport in nonepithelial cells is mediated by members of the CAT family. CAT-1 (SLC7A1) is ubiquitously expressed including kidney and intestine. Expression of CAT-1 appears to be confined to the basolateral membrane and appears to be more prominent in the medulla. This could explain why the cationic amino acid transporter CAT-1 cannot replace the function of y_LAT1 in patients with lysinuric protein intolerance. 4F2hc/xCT (SLC7A11) is a heteromeric transporter involved in the defense against oxidative stress. It exchanges glutamate and cystine. A recent report suggests the presence of this transporter in the apical membrane of enterocytes and renal epithelial cells. These results are at variance with the basolateral distribution of 4F2hc reported in other studies.
CHEMICAL STRUCTURE AND IMAGES
The general features of HATs are as follows:
• The heavy subunits (molecular mass of ~90 and ~80 kDa for rBAT and 4F2hc, respectively)are type II membrane N-glycoproteins with a single transmembrane domain, an intracellular NH2 terminus, and an extracellular COOH terminus significantly homologous to insect and bacterial glucosidases.
• The light subunits (~50 kDa) are highly hydrophobic and not glycosylated. This results in anomalously high mobility in SDSPAGE (35–40 kDa). Recent cysteine-scanning mutagenesis studies support a 12-transmembrane-domain topology, with the NH2 and COOH terminals located inside the cell and with a reentrant-like structure in the intracellular loop IL2-3 for xCT, as a model for the light subunits of HATs.
• The light and the corresponding heavy subunit are linked by a disulfide bridge. For this reason, HATs are also named glycoprotein-associated amino acid transporters. The intervening cysteine residues are located in the putative extracellular loop EL3-4 of the light subunit and a few residues away from the transmembrane domain of the heavy subunit.
• The light subunit cannot reach the plasma membrane unless it interacts with the heavy subunit.
• The light subunit confers specific amino acid transport activity to the heteromeric complex (LAT1 and LAT2 for system L isoforms, y+LAT1 and y+LAT2 for system y+L isoforms, asc1 and asc2 for system asc isoforms, xCT for system xc – isoforms, b0,+AT for system b0,+ isoforms, and AGT-1 for a system serving aspartate and glutamate transport). Moreover, reconstitution in liposomes shows that the light subunit b0,+AT is fully functional in the absence of the heavy subunit rBAT.
•HAT transport activities are, with the exception of system asc isoforms, tightly coupled amino acid antiporters.
Here the transporter is composed by one heavy (rBat) and one light (bo,+AT) subunit; this heterodimer is called bo,+ system. The bo,+ system exchanges cystine and basic aa (influx) for neutral aa (efflux). Cystine and arginine have a micromolar affinity for the system. A defect in its transporter activity causes the the reduction of kidney reabsorption of cystine and basic aa and, as a consequence, their hyper-concentration in urine (Cistinuria).
Mutations in the SLC3A1 gene encoding the glycoprotein rBAT cause cystinuria type I, whereas mutations in the SLC7A9 gene have been demonstrated in non-type I cystinuria; the gene products of SLC3A1 and SLC7A9 form the two subunits of the apical renal heterodimeric cystine transport system rBAT/b0,+AT (The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria).
Structural features of human BAT1
Heteromeric amino acid transporters: biochemistry, genetics, and physiology
The genetics of heteromeric amino acid transporters
In the kidney, rBAT/b0,+AT corresponds to the basic system that is shared by cystine.
The rBAT protein is relatively weakly expressed in the proximal convoluted tubule but strongly expressed in the proximal straight tubule. The b0,+AT protein in contrast shows the highest expression in the early segments of the proximal tubule but is almost undetectable in the proximal straight tubule. All of b0,+AT was bound to rBAT, but significant amounts of rBAT, particularly in the proximal straight tubule, were associated with an unknown light chain. Because cystine is mainly reabsorbed in the early sections of the proximal tubule, this indicates that rBAT/b0,+AT is the major cystine transporter in the kidney. This notion is supported by the clearance of cystine in cystinuria having the same value as that of a
solute which is not being reabsorbed; rBAT is rapidly degraded if not complexed with a light chain. The strong expression of rBAT in the proximal straight tubule, as a result, is likely to reflect expression of an unknown heterodimer. It is tempting to speculate that this eterodimer is the Na+-stimulated transporter for cationic amino acids. Interestingly, rBAT/b0,+AT consistently shows slightly higher transport activity in the presence of Na+ than in its absence, demonstrating its potential to mediate Na+-stimulated transport.
Expression of rBAT is regulated by nutritional signals. Surprisingly, aspartate is a particularly good inducer of the cationic amino acid transporter subunit rBAT.
Linkage and mutation analysis demonstrated that mutations in rBAT and b0,_AT cause cystinuria. To date, more than 100 mutations have been described in the rBAT protein and 66 in the b0,+AT protein. Most mutations in rBAT appear to affect the trafficking of the complex; however, some mutations also affect the transport mechanism of the heterodimer. Although cystinuria has been divided into three different clinical phenotypes, these appear to merge into mutations associated with the rBAT/b0,_AT heterodimer. Closer characterization of genotype-phenotype correlation revealed that heterozygotes with mutations in SLC3A1 have urinary amino acid levels within the control range and hence confined to type I. Mutations in SLC7A9, in contrast, showed all three clinical phenotypes. The majority of the heterozygotes have increased levels of cystine and basic amino acids, and a smaller group (14%) has amino acid levels within the control range. As a result, a new classification of cystinuria based on the genotype has been suggested. According to this classification, individuals with mutations
in SLC3A1 are categorized as type A, and individuals with mutations in SLC7A9 are categorized as type B. There is little indication for additional cystinuria genes. Only 3% of all patients do not have detectable mutations in the SLC3A1 or SLC7A9 gene, but the promoter regions and complete introns have not been sequenced in all cases. The rBAT protein is thought to interact with an unknown protein in the proximal straight tubule, which could be
a candidate gene for type I dibasic aminoaciduria. However, amino acid hyperexcretion is similar in SLC3A1/SLC3A1 as in SLC7A9/SLC7A9 genotypes, arguing against an association of rBAT with another cationic amino acid transporter of the proximal straight tubule.
Diagnostic is based on stone analysis by infrared spectroscopy or microscopic examination of urine which may reveal typical cystine crystals. Quantitative cystine excretion, which may be assessed by aminoacid chromatography, is higher in cystinic patients. Molecular approach can identify mutations which are responsible of this pathology. Medical treatment is mainly based on hydratation and urine alkalinisation, with the addition of thiol derivative only in refractory cases. Follow-up based on pH and specific gravity determination in urine samples and cystine crystal volume measurement are used to optimally monitor the medical treatment of cystinuric patients. Even with medical management, long-term outcome is poor due to insufficient efficacy and low patient compliance. Many patients suffer from renal insufficiency as a result of recurrent stone formation and repeated surgical procedures (Cystinuria: from diagnosis to follow-up).
Apical transporters for neutral amino acids: physiology and pathophysiology.
Amino Acid Transport Across Mammalian Intestinal and Renal Epithelia
Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification
Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine