Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity.
Members of the newly discovered glycoprotein-associated amino acid transporter family (gpaAT-family) share a similar primary structure with >40% identity, a predicted 12-transmembrane segment topology and the requirement for association with a glycoprotein (heavy chain) for functional surface expression. Five of the six identified gpaATs (light chains) associate with the surface antigen 4F2 heavy chain (4F2hc = CD98), a ubiquitous plasma membrane protein induced in cell proliferation, and which is also highly expressed at the basolateral surface of amino acid transporting epithelia. The differing tissue localizations of the 4F2hc-associated gpaATs appear to complement each other. As yet, a single gpaAT (b(0,+)AT) has been shown to associate with rBAT, a 4F2hc-related glycoprotein mainly localized in intestine and kidney luminal brush-border membranes. The transport characteristics of gpaATs have been shown, by expression in heterologous systems, to correspond to the previously described transport systems L, y+L, xc- and b(o,+). These (obligatory) exchangers of broad substrate specificity (with the exception of xCT) are expected to equilibrate the concentrations of their substrate amino acids across membranes. Thus, the driving force provided by a transmembrane gradient of one substrate amino acid, such as that generated by a parallel functioning unidirectional transporter, can be used by a gpaAT to fuel the secondary active vectorial transport of other exchangeable species. Vectorial transport of specific amino acids is also promoted by the intrinsic asymmetry of these exchangers. The fact that genetic defects of the epithelial gpaATs b(0,+)AT and y+LAT1 cause non-type I cystinuria and lysinuric protein intolerance, respectively, demonstrates that these gpaATs perform vectorial secondary and/or tertiary active transport of specific amino acids in vivo.
Verrey
F
F
Institute of Physiology, University of Zürich, Switzerland. verrey@physiol.unizh.ch
Meier
C
C
Rossier
G
G
Kühn
L C
LC
D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D027261:Fusion Regulatory Protein-1; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D015703:Antigens, CD; D002352:Carrier Proteins; D027261:Fusion Regulatory Protein-1; D006023:Glycoproteins