Cloning and expression of a b(0,+)-like amino acid transporter functioning as a heterodimer with 4F2hc instead of rBAT. A new candidate gene for cystinuria.
We have cloned a transporter protein from rabbit small intestine, which, when coexpressed with the 4F2 heavy chain (4F2hc) in mammalian cells, induces a b(0,+)-like amino acid transport activity. This protein (4F2-lc6 for the sixth member of the 4F2 light chain family) consists of 487 amino acids and has 12 putative transmembrane domains. At the level of amino acid sequence, 4F2-lc6 shows significant homology (44% identity) to the other five known members of the 4F2 light chain family, namely LAT1 (4F2-lc1), y(+)LAT1 (4F2-lc2), y(+)LAT2 (4F2-lc3), xCT (4F2-lc4), and LAT2 (4F2-lc5). The 4F2hc/4F2-lc6 complex-mediated transport process is Na(+)-independent and exhibits high affinity for neutral and cationic amino acids and cystine. These characteristics are similar to those of the b(0,+)-like amino acid transport activity previously shown to be associated with rBAT (protein related to b(0,+) amino acid transport system). However, the newly cloned 4F2-lc6 does not interact with rBAT. This is the first report of the existence of a b(0,+)-like amino acid transport process that is independent of rBAT. 4F2-lc6 is expressed predominantly in the small intestine and kidney. Based on the characteristics of the transport process mediated by the 4F2hc/4F2-lc6 complex and the expression pattern of 4F2-lc6 in mammalian tissues, we suggest that 4F2-lc6 is a new candidate gene for cystinuria.
Rajan
D P
DP
Department of Biochemistry, Medical College of Georgia, Augusta, Georgia 30912, USA.
Kekuda
R
R
Huang
W
W
Wang
H
H
Devoe
L D
LD
Leibach
F H
FH
Prasad
P D
PD
Ganapathy
V
V
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems; D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D003553:Cystine / Q000378:metabolism; D003555:Cystinuria / Q000235:genetics*; D019281:Dimerization; D027261:Fusion Regulatory Protein-1; D007421:Intestine, Small / Q000378:metabolism; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009865:Oocytes; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013379:Substrate Specificity; D014982:Xenopus laevis
C122153:4F2-lc6 protein, Oryctolagus cuniculus; D026905:Amino Acid Transport Systems; D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D015703:Antigens, CD; D002352:Carrier Proteins; D027261:Fusion Regulatory Protein-1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C082087:rBAT protein, Oryctolagus cuniculus; D003553:Cystine; D000409:Alanine