Function and structure of heterodimeric amino acid transporters

Abstract

Heterodimeric amino acid transporters are comprised of two subunits, a polytopic membrane protein (light chain) and an associated type II membrane protein (heavy chain). The heavy chain rbAT (related to b(0,+) amino acid transporter) associates with the light chain b(0,+)AT (b(0,+) amino acid transporter) to form the amino acid transport system b(0,+), whereas the homologous heavy chain 4F2hc interacts with several light chains to form system L (with LAT1 and LAT2), system y(+)L (with y(+)LAT1 and y(+)LAT2), system x (with xAT), or system asc (with asc1). The association of light chains with the two heavy chains is not unambiguous. rbAT may interact with LAT2 and y(+)LAT1 and vice versa; 4F2hc may interact with b(0,+)AT when overexpressed. 4F2hc is necessary for trafficking of the light chain to the plasma membrane, whereas the light chains are thought to determine the transport characteristics of the respective heterodimer. In contrast to 4F2hc, mutations in rbAT suggest that rbAT itself takes part in the transport besides serving for the trafficking of the light chain to the cell surface. Heavy and light subunits are linked together by a disulfide bridge. The disulfide bridge, however, is not necessary for the trafficking of rbAT or 4F2 heterodimers to the membrane or for the functioning of the transporter. However, there is experimental evidence that the disulfide bridge in the 4F2hc/LAT1 heterodimer plays a role in the regulation of a cation channel. These results highlight complex interactions between the different subunits of heterodimeric amino acid transporters and suggest that despite high grades of homology, the interactions between rbAT and 4F2hc and their respective partners may be different.

Molecular and ionic mimicry and the transport of toxic metals

“…These findings suggest that testicular uptake of Cd 2+ may be due to the activity of a Zn 2+ -transporter, as well as a transporter that carries thiol-conjugates of Cd 2+ (possibly as G-S-Cd-S-G or Cys-S-Cd-S-Cs). The latter may be an amino acid transporter, of which many have been identified in the testes (Wagner et al, 2001). Subsequent studies of the interaction between Zn 2+ and Cd 2+ provided additional evidence for the participation of a Zn 2+ carrier protein in the transport of Cd 2+ (Waalkes and Perantoni, 1988).…”

“…Although transporters for GSSG (multidrug resistance proteins 1 and 2) have been identified in the canalicular membrane (Akerboom et al, 1984(Akerboom et al, , 1991Keppler et al, 1998;Leslie et al, 2001), they have not been localized in the sinusoidal membrane. Furthermore, various amino acid carriers have been identified in the liver (Bode, 2001;Wagner et al, 2001); however, it is presently unclear whether these carriers are present on the sinusoidal membrane.…”

“…Once in the biliary tree, CH 3 Hg-S-G appears to be catabolized to yield CH 3 Hg-S-Cys, which can be reabsorbed by cells lining the bile ducts and the enterocytes in the intestine (Dutczak and Ballatori, 1992). Though the actual mechanism(s) involved in this uptake have yet to be determined, it is reasonable to hypothesize that CH 3 Hg-Cys acts as a mimic of an amino acid at the site of an amino acid transporter, such as system L. A number of amino acid transporters, including system L (LAT3; Babu et al, 2003), have been identified in the liver (Bode, 2001;Wagner et al, 2001); however, the exact localization of any one of them has not yet been determined.…”

Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK

“…The amino acids are taken up through the brush border membrane and exit the epithelial cells through the basolateral membrane to the interstitial space. Two heteromeric amino acid transport exchangers (systems b o,ϩ and y ϩ L) have a major role in the reabsorption of cystine and dibasic amino acids (2)(3)(4). First, the heterodimer formed by rBAT and b o,ϩ AT is the amino acid transporter b o,ϩ , which mediates high-affinity uptake of cystine and dibasic amino acids coupled with the efflux of neutral amino acids (5)(6)(7)(8) at the apical membrane of epithelial cells of the proximal tubule (9).…”

Aromatic Amino Acid Transporter AAT-9 of Caenorhabditis elegans Localizes to Neurons and Muscle Cells

“…In addition to a catalytic subunit (the light chain), there is a type II glycoprotein subunit (the heavy chain). The light chain must associate with the heavy chain for functional expression at the cell surface (2)(3)(4)(5)(6)(7). This association is stabilized by a disulfide bridge formed between two highly conserved cysteine residues (7).…”